Reflectance Confocal Microscopy in Basal Cell Carcinoma

Study Overview
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Brief Summary
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Skin cancer is the most common cancer and its incidence is increasing rapidly. The rising number of skin cancer may result in long waiting lists for consultation at departments for dermatological care and in increasing health care costs. In case of suspicion on skin cancer it is of utmost importance to diagnose and treat in an early phase, preferable in a patient friendly manner. Skin cancer comprises melanoma and non-melanoma skin cancer (NMSC: basal cell carcinoma (BCC), squamous cell carcinoma (SCC) and its precursors actinic keratosis (AK) and Bowen disease). As BCC is the most common skin cancer type with an estimated incidence of 51,000 new tumors in 2015 (The Netherlands), this study will focus on this skin cancer type. In case of suspicion on BCC, at present, the pathological examination of a biopsy is the gold standard for diagnosing a BCC. With the implementation of non invasive diagnosis by reflectance confocal microscopy (RCM) in routine patient care settings the diagnosis can be assessed at the first consultation in a non-invasive way and the patient can be treated instantly. Overall, the aim of this study is to investigate whether reflectance confocal microscopy can correctly identify the subtype of basal cell carcinoma. Study design: Randomized controlled trail. Comparison with usual care: punch biopsy and excision.

Detailed Description
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INTRODUCTION AND RATIONALE: Skin cancer is the most common cancer and its incidence is increasing rapidly in Western countries. In the Netherlands the registry of skin cancer is poor, however based on recent literature and guidelines the investigators estimate the number of new malignant skin tumors and the precursor actinic keratosis (AK) in 2015 at around 235,278, having a major impact on the health care system. Moreover, it is predicted that numbers of skin cancer will rise with 4.5-8% per year, depending on the type of skin cancer. Skin cancer comprises melanoma and non-melanoma skin cancer (NMSC: basal cell carcinoma (BCC), squamous cell carcinoma (SCC) and its precursors actinic keratosis (AK) and Bowen disease). In case of suspicion on NMSC, at present, the pathological examination of a biopsy is the gold standard. In case of clinical suspicion on AK, the diagnosis is made à vue, without pathological confirmation. In the United States, already in 2003, skin cancer was found to be among the most costly of all cancers to treat, thus, it is evident that skin cancer places an enormous burden on western healthcare systems with increasing costs. As BCC is the most common skin cancer (about 75% of all skin cancers) with an estimated incidence of 51,000 new tumors in 2015, this study will focus on this skin cancer type. HEALTH CARE EFFICIENCY PROBLEM: As described above, the incidences of the various malignant skin tumours are increasing dramatically. The rising number of skin cancer may result in long waiting lists for consultation at departments for dermatological care and in increasing health care costs. In case of suspicion on skin cancer it is of utmost importance to diagnose and treat in an early phase, preferable in a patient friendly manner. With the implementation of reflectance confocal microscopy (RCM) in routine patient care settings the diagnosis is assessed at the first consultation and the patient can be treated instantly. A second consultation for explaining the diagnosis is than not necessary, which time can then be used for other new patients. Also, with the conventional diagnostic procedure (pathological investigation of a skin biopsy) the investigators experience in 29% of the cases a sample error, so the BCC subtype is not correctly identified, and as treatment depends on BCC subtype many patients need a subsequent treatment because of treatment failure or recurrence. Also for pathologists, to examine skin tumor after skin tumor is not that efficient and challenging. More pathologists are needed if there will not be other diagnostic techniques in the future. RCM will also, not unimportantly, lower the costs for diagnosing skin cancer. USUAL CARE: Currently, in case of suspicion on NMSC, including BCC, an invasive diagnostic biopsy for pathological examination is performed.Treatment choices depend on BCC subtype. THE INTERVENTION TO BE INVESTIGATED: RCM is a non-invasive imaging technique. It provides real time images of cell- and tissue structures and dynamics in situ, without the need for ex vivo tissue samples. RCM visualizes human skin up to a depth of around 250 μm. Most, but not all tumors can be visualized. For thicker tumors RCM may help to find the optimal localization to perform a biopsy, as superficial features in these tumors may help to spot these. Moreover, the whole tumor can be imaged by RCM and a diagnosis can be made instantly. RCM features for skin cancer are reported, which showed a high correlation with conventional pathological features. These features allow to diagnose AK and SCC, and subtypes in BCC (superficial, nodular, micronodular, infiltrative and mixed type BCCs). RCM in the RELEVANCE FOR PRACTICE Skin cancer is responsible for 50% of the costs in dermatological patient care, 75-80% of these costs are caused by BCC. These costs will increase even more, as incidence rates will rise further. As described above, the gold standard is pathological investigation of a biopsy or of an excision. However, pathological diagnosis of a biopsy often results in sampling errors, as only a small part of the tumor is investigated resulting in potentially inappropriate chosen therapies. The subtypes of BCC are treated differently. As a sample error may lead to treatment failures or recurrences, other subsequent treatments are needed, increasing costs. In addition, the conventional method is unfriendly for patients, as it is invasive, painful, scarring, and the diagnosis is not instantly available. In order to implement patient friendly RCM in daily BCC care, a large prospective study is needed. The ability of RCM in determining the correct diagnosis and subtyping BCC needs to be investigated as well as preparing protocols for use in patient care. It is believed that this diagnostic imaging technique will be more cost-effective and more patient friendly as compared to the biopsy procedure, the gold standard at present. Therefore, the purpose of this study is to investigate whether reflectance confocal microscopy can correctly identify the subtype of basal cell carcinoma. Study design: Randomized controlled trail. Comparison with usual care; punch biopsy and excision.

Official Title
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In Vivo Reflectance Confocal Microscopy, a Novel Non-invasive Tool for Diagnosing Skin Cancer - A Randomized Controlled Trial

Conditions
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Carcinoma, Basal Cell

Intervention / Treatment
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* Device: Reflectance confocal microscopy
* Procedure: Punch biopsy
* Procedure: Surgical excision


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients must be able to adhere to all requirements of the study Patients must be willing to give written informed consent Clinically diagnosed/ clinical suspicion of basal cell carcinoma Exclusion Criteria: Participating in other investigational research currently or in the previous 28 days before the study Patient is having a medical condition which excludes participating the research, according to the investigator Incapacitated subjects will not be included Lesion(s) on parts of the body which do not allow to adequately image the tumour with RCM.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Diagnostic
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Standard of care procedure<br>Clinical suspected basal cell carcinomas, of all subtypes, will be diagnosed by conventional 3mm punch biopsy of the most clinical suspicious part of the lesion. Punch biopsies will be performed under local anesthetics using 1% xylocaine/adrenaline. Hematoxylin/eosin stained sections of the punch biopsies will be evaluated by an experienced pathologist. Subjects will receive surgical excision according to subtype. When there is any doubt by reflectance confocal microscopic diagnosis, a punch biopsy will also be obtained and the lesion will be excized when the biopsy reveals a basal cell carcinoma. | Procedure: Punch biopsy<br>* Obtaining a skin sample of the suspicious lesion under local anesthetics<br>* Other names: Biopsy;Procedure: Surgical excision<br>* Excision of the basal cell carcinoma lesion under local anesthetics<br>* Other names: Surgery;|
| Experimental: Reflectance confocal microscopy (RCM)<br>The Vivascope 1500 and Vivascope 3000 (handheld divice) will be used (CE certified, Lucid Technologies, Henrietta, NY, USA). Reflectance confocal microscopy (RCM) imaging will be performed on clinical suspected basal cell carcinomas, of all subtypes. When there are signs of a basal cell carcinoma imaged by RCM, subjects will receive surgical excision according to subtype. When there is any doubt by RCM diagnosis, a punch biopsy will also be obtained and the lesion will be excized when the biopsy reveals a basal cell carcinoma. | Device: Reflectance confocal microscopy<br>* Non-invasive imaging of the lesion<br>* Other names: Vivascope 3000;Procedure: Surgical excision<br>* Excision of the basal cell carcinoma lesion under local anesthetics<br>* Other names: Surgery;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The number of correctly identified basal cell carcinoma and the subtype by Reflectance confocal microscopy validated by histopathological examination of the excision specimen |  | Through study completion, an average of 3 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Quality of life (Qol) | VAS (Visual analogue scale) | Through study completion, an average of 3 years | 
| Cost effectiveness of Reflectance confocal microscopy as diagnostic tool to diagnose basal cell carcinoma | Productivity Cost Questionnaire (IMCQ, generic instrument for measuring medical costs) | Through study completion, an average of 3 years | 
| Quality Adjusted Live Years (QALY's) | EQ-5D-5L health questionnaire | Through study completion, an average of 3 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Reflectance confocal microscopy, Basal cell carcinoma, Biopsy, Diagnostics