This is an open-access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work, first published in JMIR Research Protocols, is properly cited. The complete bibliographic information, a link to the original publication on http://www.researchprotocols.org, as well as this copyright and license information must be included.
Basal cell carcinoma (BCC) is the most common cancer diagnosed in white populations worldwide. The rising incidence of BCC is becoming a major worldwide public health problem. Therefore, there is a need for more efficient management.
The aim of this research is to assess the efficacy and safety of a one-stop-shop (OSS) concept, using real-time
This is a prospective non-inferiority multi-center RCT designed to compare the “OSS concept using RCM” to current standards of care in diagnosing and treating clinically suspected BCC. Patients ≥ 18 years attending our outpatient clinic at the Department of Dermatology, Academic Medical Center, University of Amsterdam, and the Department of Dermatology, the Netherlands Cancer Institute-Antoni van Leeuwenhoek Hospital (Amsterdam, The Netherlands) with a clinically suspected new primary BCC lesion will be considered for enrollment using predefined inclusion and exclusion criteria, and will be randomly allocated to the experimental or control group. The main outcome parameter is the assessment of incomplete surgical excision margins on the final pathology report of confirmed BCC lesions (either by punch biopsy or RCM imaging). Other outcome measures include diagnostic accuracy (sensitivity and specificity) of RCM for diagnosing BCC and dividing between subtypes, and throughput time. Patient satisfaction data will be collected postoperatively after 3 months during routine follow-up.
This research is investigator-initiated and received ethics approval. Patient recruitment started in February 2015, and we expect all study-related activities to be completed by fall 2015.
This RCT is the first to examine an OSS concept using RCM for diagnosing and treating clinically suspected BCC lesions. Results of this research are expected to have applications in evidence-based practice for the increasing number of patients suffering from BCC and possibly lead to a more efficient disease management strategy.
ClinicalTrials.gov: NCT02285790; https://clinicaltrial.gov/ct2/show/NCT02285790 (Archived by WebCite at http://www.webcitation.org/6b2LfDKWu).
Basal cell carcinoma (BCC) is the most common cancer diagnosed in white populations worldwide. The rising incidence of BCC is becoming a major worldwide public health concern [
Clinically, BCC are characterized by small, translucent, or pearly papules, with raised teleangiectatic edges [
The use of real-time
In 2012, van der Geer et al reported on the feasibility of a one-stop-shop (OSS) concept for the treatment of skin cancer patients [
The aim of our study is to assess the efficacy and safety of the OSS concept, using real-time
Patients will be recruited from the outpatient clinics of the Department of Dermatology, Academic Medical Center, University of Amsterdam (AMC), and the Department of Dermatology, the Netherlands Cancer Institute-Antoni van Leeuwenhoek Hospital (AVL), second-line and third-line reference centers. Consecutive patients with clinically suspected new primary BCC will be prospectively enrolled and randomly assigned to either the experimental (RCM-OSS) or control (standard of care) group during times the study associates will be available. Clinical assessment will be performed by an experienced, board-certified dermatologist. Clinical and dermoscopy pictures of the BCC lesion will be taken by a medical photographer. Patients with multiple clinically suspected new primary BCC lesions will be included for only the lesion most suitable for conventional surgical treatment according to the following order: (1) chest, (2) extremities, and (3) head and neck area.
The inclusion criteria are the following:
patient with clinically suspected new primary BCC as assessed by an experienced board certified dermatologist, (2) age ≥18, (3) patient is willing and able to give written informed consent, (4) BCC lesion is suitable for conventional surgical excision under local anesthetics, and (5) BCC lesion has been present for at least 1 month.
The exclusion criteria are the following: (1) BCC lesion in a high-risk location of the face (H-zone and ears), (2) contra-indication for conventional surgical excision (primary surgical closure seems not achievable), (3) recurrent BCC lesion (BCC that has been previously unsuccessfully treated), (4) macroscopic ulcerating BCC lesions (not feasible for RCM analysis due to technical reasons), (5) patient with basal cell nevus syndrome, (6) patient treated with hedgehog inhibitor medication, (7) patient with a history of hypersensitivity and/or allergy to local anesthesia, (8) patient unavailable in the following 6 weeks (for example due to holidays or sports), and (9) patient not able to understand the procedures involved.
The investigators will enrol subjects at both study locations (AMC and AVL). Included patients with clinically suspected new primary BCC lesions will be randomly allocated to the different diagnostic procedures. The investigators will obtain the patient’s consent. Each consecutive patient will be assigned a randomization number according to a computer-generated randomization list (ALEA) using random block sizes of 2, 4, 6, and 8 to ensure treatment concealment. Randomization will take place between the control and experimental group. This study will have an open label set-up. The patient and local investigator will not be blinded.
The randomization will be blinded. The pathologists analyzing the final excision specimen will be blinded to the patient’s history and to the results of RCM imaging. Whenever the histology of the punch biopsy is not required in the diagnostic process of the final excision specimen, the pathologist will also be blinded for those results. After initial RCM diagnosis by the study associates (DK and YE), two independent outcome assessors (M. Ulrich, Charite Berlin in Germany and C. Longo, Modena and Reggio Emilia in Italy) analyzing the RCM images will be blinded to the patient’s history and to the results of the final pathology report (reference standard).
We chose a cutoff of 95% as an acceptable radical BCC excision rate with standard of care based on our experience. Using the Miettinen and Nurminen confidence interval around the risk difference (24), with two groups of 38 patients, we will have 80% power to assess noninferiority of the OSS concept with RCM over usual care, considering an expected radical BCC excision rate of 95% in both arms, a noninferiority limit (delta) of 15%, and a one-sided alpha of 0.05.
Incomplete surgical excision on the final pathology report of a routinely processed tissue specimen of confirmed BCC lesions (either by punch biopsy or RCM imaging) is the main outcome parameter. Assessment will be performed by an experienced board-certified pathologist. The number of incomplete excisions will be compared between the experimental and control group. Other assessments of included subjects with confirmed BCC lesions (either by punch biopsy or RCM imaging) will include the following:
Diagnostic accuracy (sensitivity and specificity) of the RCM for BCC diagnosing and subtyping will be separately analyzed by comparing RCM diagnosis and subtype with final pathology reports of the experimental group. This will be performed by using unidentifiable saved RCM images of all included lesions of the experimental group to analyze inter and intraobservership variability in the interpretation of RCM imaging. The study associates (DK and YE) and two independent outcome assessors (MU and CL) will be blinded to the patient’s history and to the results of the final pathology report (reference standard).
Throughput time will be assessed by the study associates and compared between the experimental and control group.
Patient satisfaction will be assessed postoperatively 12 weeks after excision by using a standardized web-based questionnaire for patient reported outcomes in the management of skin diseases. An adjusted version of this web-based questionnaire has previously been published to assess patient satisfaction among patients suffering from psoriasis [
The frequency of and reasons for exclusions will be documented.
The frequency of interpretable, indeterminate, and intermediate tests will be documented.
Adverse events during the procedure will be documented.
BCCs will be divided into 5 main subtypes based on the histopathological growth pattern of the final excision specimen: superficial (sBCC), nodular (nBCC), micronodular (mnBCC), infiltrating (iBCC), and basosquamous (bBCC). In the case of mixed-type diagnosis, defined as two or more single growth patterns, the histology will be classified into single subgroups determined by the most aggressive component of the pathological feature according to the descending gradation from bBCC, iBCC, mnBCC, nBCC, to sBCC. The most aggressive component will determine the excision margin (5 mm versus 3 mm).
After obtaining written informed consent, the screening will be completed. Patients with clinically suspected new primary BCC lesions will be randomly allocated to the following regimes:
Experimental group (N=38): Clinically suspected new primary BCC lesions will be diagnosed and divided into subtypes using RCM imaging (Vivascope 1500; Lucid Technologies, Henrietta, NY, USA) according to a standardized protocol [
Control group (N=38): Clinically suspected new primary BCC lesions will be diagnosed and divided into subtypes according to current standards of care. A conventional 3 mm punch biopsy will be performed in the most elevated part of the lesion using local anesthetics (1% xylocaine/adrenaline). A biopsy specimen will be analyzed by a pathologist (within 2 weeks). After diagnosis, excision of the BCC lesions with adequate margins will be performed within the following 4 weeks according to current standards of care. Clinically suspected primary BCCs that are not confirmed by punch biopsy will also receive surgical treatment with a margin of 3 mm.
The study design incorporated five parts. First, screening took place. Second, intake involved the following steps: written informed consent, intake, randomization, and photo documentation. Third, allocation to the experimental or control group consisted of (1) assessment of diagnosis and subtyping of clinically suspected new primary BCC, and (2) assessment of surgical margins. Fourth, surgical excision of the lesion took place: the excised surgical specimen was assessed by the pathologist and an assessment of throughput time was conducted. Finally, a routine 12-week postoperative control visit was conducted, involving an assessment of patient satisfaction using the web-based questionnaire (
Expected RCM features of different BCC subtypes as previously reported in the literature.
Subtype | Epidermis | DEJa | Upper dermis |
sBCC | Epidermal streaming |
cords connected to the epidermis that may occasionally display clefting and peripheral palisading of nuclei |
thin blood vessels parallel to the en-face plane of RCM imaging |
|
|
OR |
|
|
|
dark silhouettes embedded in stroma of thickened collagen |
|
|
|
dilated blood vessels coursing parallel to en-face plane of imaging |
|
nBCC | Possible ulceration |
increase in vascular diameter without cords connected to the epidermis |
rounded to polycyclic basaloid bright tumor islands ( |
mnBCC | Possible ulceration |
increase in vascular diameter without cords connected to the epidermis |
rounded to polycyclic basaloid bright tumor islands ( |
iBCC |
|
increase in vascular diameter without cords connected to the epidermis |
the absence of small or big tumor islands |
bBCC |
|
no features previously reported |
no features previously reported |
adermal epidermal junction
Data will be recorded on data entry forms and will be entered in a computer system for subsequent tabulation and statistical analysis. The data will be handled confidentially and anonymously. Furthermore, all information relevant to the treatment will be recorded in the electronic medical file.
All data will be collected and transferred to a Microsoft Excel database. The statistical analysis will be performed at the AMC using SPSS version 21.0. We will calculate the observed difference as the proportion of radical BCC excisions in the care-as-usual arm minus this proportion in the OSS with RCM arm, and calculate a one-sided 95% (or two-sided 90%) confidence interval for this difference using the Miettinen and Nurminen method [
This is an investigator-initiated unfunded prospective open-label noninferiority randomized controlled multicenter trial. Development of the project commenced in fall 2012, and the study protocol has been approved by the ethics committee at the coordinating center (AMC, METC 2014_244) and by the local Institutional Review Board at the participating center (AVL) in fall 2014. This trial has also been registered publically at ClinicalTrials.gov (identification number: NCT02285790). Patient recruitment started in February 2015, and the expected date of completion is fall 2015.
The study is being conducted according to the principles of the Declaration of Helsinki (Fortaleza, Brazil, October 2013) and in accordance with the Medical Research Involving Human Subjects Act (WMO) and other relevant guidelines, regulations, and acts.
BCC is the most prevalent skin cancer, and its prevalence is increasing [
Subjects participating in the study will be informed and will have to provide written informed consent prior to enrollment. Study participation will not result in additional follow-up visits other than clinically required 3 months postoperative.
Real-time
Thus, there is a potential benefit for the participating subject, namely noninvasive confirmation of clinically suspected BCC lesions followed by direct surgical treatment. Considering the relatively quick and simple procedure, noninvasiveness of the diagnostic method, and the one-stop-shop concept of diagnosing and treating BCC at the same consultation, the balance between burden, possible side effects, and prospect for improvement might be very favorable.
This RCT is the first to examine an OSS concept using RCM for diagnosing and treating clinically suspected BCC lesions. Results of this research are expected to have applications in evidence-based practice for the increasing number of patients suffering from BCC, and possibly lead to a more efficient disease management strategy.
Patient satisfaction questionnaire.
None declared.