Randomized controlled trial to evaluate the effects of ethyl-2-cyanoacrylate on pain intensity and quality of life in head and neck cancer patients suffering from cetuximab-induced rhagades during radioimmunotherapy: the support trial

Cetuximab is a chimeric monoclonal antibody against the epidermal growth factor receptor (EGFR). It has shown clinical activity against a variety of malignancies [1–5]. In head and neck cancer cetuximab is approved in combination with radiotherapy as a curative treatment option for patients with locally advanced squamous cell carcinoma of the head and neck (LASCCHN). In the pivotal phase III trial published by Bonner et al., a radioimmunotherapy with cetuximab resulted in a higher response rate, an improvement of the duration of locoregional control and an increased rate of 5-year overall survival [6–9]. Cetuximab, as with the entire class of anti-EGFR inhibitors is associated with a high prevalence of dermatological side effects [10–15]. Commonly experienced dermatological side effects include acneiform rash, hair changes, enhancement of radiation-induced dermatitis, pruritus, mucositis, xerosis cutis, rhagades and paronychia. While acneiform rash is the most common side effect during the first weeks of application of the monoclonal antibody cetuximab, xerosis of the skin and xerosis-associated rhagades usually develop after at least 5 to 6 weeks of treatment with an anti-EGFR inhibitor such as cetuximab [15–17]. In the European literature fissures of the skin and skin cracking are termed rhagades [18]. Rhagades of the fingertips and toes, of the palms or knuckles, the heels, the soles and especially of the interphalangeal joints are one of the most frightening and painful dermatological side effects that may develop as late phase skin reactions from EGFR-inhibitor therapy [19]. Rhagades occur in about 15% to 25% of all patients treated with an EGFR-inhibitor and are characterized by pain, severe tenderness and poor healing tendency. They can be very painful and, furthermore, may create a risk for local or systemic infection [16, 17]. All of those dermatological toxicities including cetuximab-induced rhagades have often led to reduction or even cessation of an effective anticancer therapy and they have been shown to decrease patients' quality of life (QoL) significantly. Activities of daily living (ADL) may be impaired due to skin reactions, especially due to anti-EGFR induced painful rhagades. Whereas prevention and treatment recommendations for cetuximab-induced acneiform rash are well established today and have been published from several research groups recently [13–24], treatment recommendations for the treatment of cetuximab-induced painful rhagades are only reported anecdotally [15–18]. Lacouture et al. published general recommendations for the prevention and treatment of rhagades recently based on their own expert opinion. The individual recommendations for prevention of rhagades include the wearing of protective footwear or covering the fingertips to avoid friction; for treatment the authors recommended the topical application of thick moisturizer, zinc oxide creams, propylene glycol 50% solution, salicylic acid 10% ointment, steroid tapes and hydrocolloid dressings or liquid glues like cyanoacrylate preparations to keep the rhagades from worsening [17]. Limited evidence also supports the use of silver nitrate or potassium permanganate foams and topical antibiotics [17]. Oral antibiotics, however, may be necessary if infection of the rhagades occurs and worsens despite topical treatment. Randomized clinical trials assessing the prevention or treatment of EGFR-induced rhagades, however, have not been performed so far. No published data are available supporting prevention or treatment recommendations for those rhagades. Thus, evidence-based treatment recommendations for anti-EGFR induced painful rhagades do not exist. All recommendations are based on individual observation, case studies and expert opinion. Another problem is that for those rhagades typically seen during and after anti-EGFR treatment no suitable classification system or scoring system is available. The NCI CTCAE criteria do not comprise a useful scoring system for this type of side effects [25]. Thus, an appropriate scoring system is warranted to classify the EGFR inhibitor induced rhagades and to allow rational treatment decisions based on a standardized clinical scoring system.

Liquid glues such as ethyl-2-cyanoacrylate (ECA), an ethyl ester of the 2-cyano-2-propenoic acid, are often used as adhesive in a variety of different work settings in industry, e.g. as a component in nail-care products such as nail glue. Besides, ECA is commonly used for various medical indications, especially for the treatment of wounds, e.g. for liquid bandages in children and for suture-less surgery. It is a colorless liquid with low viscosity at normal room temperature and it polymerizes rapidly in the presence of moisture. Wound healing can be accelerated with ECA [12, 17, 26–28]. ECA is suitable for the treatment of rhagades due to the direct proportional influence of the OH-group concentration of ECA on the age hardening velocity which occurs within a spit second [17]. Sealing the cracks with ECA may also help to relieve pain [17, 26–28]. Furthermore, applying ECA leads to wound closure and to an effective germ barrier which may lower the rate of secondary wound infections [29]. Dermatological toxicities, especially rhagades induced by EGFR inhibitors, critically affect patients’ health-related quality of life and, as a consequence, the dose intensity of EGFR inhibitors and, thus, the effectiveness of antineoplastic regimens. There are several patients known from observation who did not receive their planned course of anticancer treatment due to severe cutaneous side effects and who, therefore, had a poorer outcome of their disease. Due to the missing data from clinical trials on the prevention and the management of EGFR-inhibitor induced rhagades, the crucial impact of rhagades on the patient’s wellbeing and QoL and the adherence to anticancer treatment, prospective, randomized, controlled clinical trials are warranted to evaluate treatment options for EGFR-inhibitor induced rhagades, which hopefully may allow the establishment of evidence-based prevention and treatment guidelines.

The SUPPORT trial is a prospective, open-label, randomized, controlled intervention trial exploring the efficacy of ethyl-2-cyanoacrylate for the treatment of painful cetuximab-induced rhagades compared to the standard treatment of each institution. In addition, the clinical usefulness of the SUPO score, a new classification system for rhagades induced by EGFR-inhibitor therapy, will be assessed and validated in a clearly defined patient cohort.

Patients with the diagnosis of LASCCHN and treated with primary definitive cetuximab-based radioimmunotherapy within the HICARE clinical trial protocol [30] will be evaluated and screened for the participation in the SUPPORT trial at the time when they develop cetuximab-induced rhagades. All patients fulfilling the inclusion and exclusion criteria will be informed about the study.

After achievement of the written informed consent patients will be 1:1 randomized in the experimental arm or the control arm. All patients will receive a specific treatment for their painful rhagades. In the experimental arm patients will be topically treated with the liquid glue ethyl-2-cyanoacrylate (ECA) whereas in the control arm patients will obtain the standard therapy of the institution. All patients will be assessed for pain, SUPO Score and QoL after 5 to 7 days, respectively.In case of insufficient response and absent clinical benefit of standard treatment of the institution in the control arm 5 to 7 days after begin of treatment a cross over to the experimental group can be performed due to ethical reasons. No statistical influence on any endpoint will be expected due to the cross over design. End of study is 5 to 7 days after first application of ECA or the standard treatment of the institution. No further follow-up visits are scheduled within the trial. The last patient included into the study will be followed for exactly 5 to 7 days after start of treatment. This is considered the final study visit. The overall duration of the trial is expected to be approximately 24 months. All participants have the right to drop out the trial at any time.

Safety and toxicity of the study treatment will be evaluated by clinical examination. The International Common Terminology Criteria for Adverse Events (CTCAE) version 4.02 will be used for toxicity and adverse event reporting. A copy or the CTCAE can be accessed from the CTEP home page: http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm.

According to the §13 of the German GCP-Regulation all important trial documents will be achieved for at least 10 years after the trial termination.

According to the §28c of the German X-ray Regulation (RöV) and the §87 of the German Radiation Protection Regulation (StrlSchV) the informed consent forms including patients consent for trial participation, application of irradiation and data transmission to the competent authority will be achieved for at least 30 years after the trial termination.

The Clinical Trials Center of the Department of Radiation Oncology will be responsible for archiving all relevant data.

The procedures set out in this trial protocol, pertaining to the conduct, evaluation, and documentation of this trial, are designed to ensure that all persons involved in the trial follow the guidelines of Good Clinical Practice (GCP) and the ethical principles described in the applicable version of the Declaration of Helsinki (2008 Version of the Declaration of Helsinki, adopted at the 59th WMA General Assembly, Seoul, October 2008), as well as in accordance with the “Berufsordnung für Ärztinnen und Ärzte” in the most recent version. The trial will be carried out in adherence to local legal and regulatory requirements.

A positive Ethics Vote was obtained from the independent Ethics Committee of the Medical Faculty of the University of Heidelberg, Germany (S-542/2010) and the local ethics committee of every participating site. The SUPPORT trial is registered at http://www.clinicaltrials.gov website, number NCT01693159.

Participation of a patient in this study is voluntary. Before being admitted to the clinical trial, the subject must consent to participate after the nature, scope, and possible consequences of the clinical trial have been explained in a form understandable to him or her. The subject must give written informed consent for study participation. A subject may voluntarily discontinue participation in this study at any time at their own request. Before study entry, patients will be informed by the written information brochure as well as orally about the planned procedures within this study, especially about potential benefits or potential risks. Informed consent will be documented by the patient's signature on the informed consent form.

In case of withdrawal of a subject at his/her own request, the reason should be asked for as extensively as possible and should be documented. All data acquired within this study will be allowed for further evaluation and inclusion into the final analysis due to written informed consent and data privacy statement.

The data obtained in the course of the trial will be treated pursuant to the Federal Data Protection Law (Bundesdatenschutz- bzw. Landesdatenschutzgesetz, BDSG, LDSG).

EGFR inhibitors such as cetuximab are associated with a unique group of class-specific cutaneous toxicities. Rhagades are one of the most painful and most dreaded complications from EGFR inhibitor therapy Currently, neither a scoring system for cetuximab-induced rhagades for diagnostics nor a standard of care for the treatment of the rhagades is established. Prevention and management of EGFR-inhibitor-related rhagades, however, is critical to maintain patients’ health-related quality of life and dose intensity of antineoplastic regimens as the pain, the discomfort and the reduced QoL caused by the rhagades can reduce compliance with anti-EGFR therapy. For this reason, exact diagnosis and appropriate treatment are very important. The SUPPORT trial is the first randomized, controlled clinical trial evaluating a new treatment option for painful cetuximab-induced rhagades. The main goal of this study is to show a superiority of ECA compared to common standard treatments for patients with LASCCHN developing painful rhagades during combined radioimmunotherapy with the monoclonal EGFR-antibody cetuximab. Since there is no scoring system for rhagades described elsewhere, the new SUPO score will be prospectively assessed in terms of clinical usefulness for the classification of EGFR inhibitor induced rhagades. An effective management of the painful rhagades is essential to assure a better quality of life for the patients, to allow a better adherence to cancer therapy and to avoid interruptions or even discontinuation of antineoplastic treatment associated with poor outcome. The results of the SUPPORT trial may help to define an evidence-based treatment approach for EGFR-inhibitor induced rhagades in the near future.