In vivo reflectance confocal microscopy, a novel non-invasive tool for diagnosing skin cancer - a randomized controlled trial

Skin cancer (SC) is the most common cancer and its incidence is increasing
rapidly in Western countries.(8-9) In the Netherlands the registry of SC is
poor, however based on recent literature and guidelines we estimate the number
of new malignant skin tumours and the precursor actinic keratosis (AK) in 2015
at around 235,278, having a major impact on our health care system. Moreover,
it is predicted that numbers of SC will rise with 4.5-8% per year, depending on
the type of skin cancer. SC comprises melanoma (MM) and non-melanoma SC (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 the
US, already in 2003, SC was found to be among the most costly of all cancers to
treat, thus, it is evident that SC places an enormous burden on western
healthcare systems with increasing costs.(1) As BCC is the most common SC with
an estimated incidence of 51,000 new tumours in 2015, with the conventional
diagnostic procedure we experience in 29% of the cases a sample error, so the
subtype is not correct. Treatment choices depend on BCC subtype, thus the
correct sub-typing is very important.
HEALTH CARE EFFICIENCY PROBLEM and RELEVANCE FOR PRACTICE
As described above, the incidences of the various malignant skin tumours are
increasing dramatically. The rising number of SC may result in long waiting
lists for consultation at departments for dermatological care and in increasing
health care costs. In case of suspicion on SC it is of utmost importance to
diagnose and treat in an early phase, preferable in a patient friendly manner.
SC 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 tumour 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 sub-typing needs to be investigated as well as
preparing protocols for use in patient care. With implementation of RCM we aim
to contribute to these demands as we believe 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. We intend, in case our
future studies demonstrate the expected advantages of RCM, to advise to adjust
guidelines with respect to our past and future results.
With the implementation of 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) we
experience in 29% of the cases a sample error (10), 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 tumour after skin tumour is not that
efficient and challenging. More pathologists are needed if we don*t try to
search for other diagnostic techniques. RCM will also, not unimportantly, lower
the costs for diagnosing SC. Currently, in case of suspicion on NMSC, including
BCC, an invasive diagnostic biopsy for pathological examination is performed.
(Guidelines NVDV)
At present, the use of RCM imaging for diagnosing SC in clinical practice is
increasing in Italy and Germany. However, in the Netherlands, the use of this
technique is only limited to research. This is mainly caused by the differences
in insurance and healthcare systems between these countries. A large scale
prospective study on assessment of the BCC subtype, which is lacking in
international literature, is needed to implement this diagnostic technique in
the Dutch healthcare system. Implementation of RCM imaging in our health care
system may result in patient friendly and instant diagnosis, cost reduction,
reduction of sampling errors, reduction of inappropriate treatment choices and
unnecessary diagnostic excisions.
Besides the patient friendliness, implementation of RCM in patient care is
important from an economic point of view. Costs for pathologist, manpower,
materials, appointments, inappropriate therapies, leading to subsequent
therapies because of treatment failures decrease. Yearly avoidable costs are
estimated for our center at ¤ 225,179. About ¤141 per BCC avoided can be saved.
Investment in RCM is about ¤250.000 and will be depreciated over 10 years.
Yearly variable cost for RCM are ¤54,000. This means reasoning from the
Radboudumc 2014 production that costs per RCM diagnosis are ¤49. From this we
infer that net savings are ¤92 per biopsy avoided (¤147.200 yearly for our
center) and even more if economies of scale are exploited nationally (¤
4692000). If in future 40-50% of all SC can be imaged by RCM, meaning on a
national basis 94000 tumours, total yearly national savings will then be around
¤ 8648000 (conservative estimate).

RESEARCH QUESTION(S): Can in vivo reflectance confocal microscopy (RCM)
correctly identify the subtype of basal cell
carcinoma (BCC)?

Primary Objective: To study whether in vivo reflectance confocal microscopy
(RCM) can correctly identify the subtype of BCC.

Primary outcome measure is defined as:
- Correct sub-typing of BCC after excision.

Secondary outcome measures:
- QoL
- Cost
- QALY's
- The ability of RCM to separate sBCC from other BCCs
- Development of guidelines and protocols for future RCM users.

Randomized controlled trial. In this design it is possible to obtain empirical
estimates of the (cost-)effectiveness in daily clinical practice, beyond the
diagnostic value. Patients with lesions clinically suspicious for BCC, eligible
for RCM, visiting the dermatological departments of the Radboud University
Medical Center, Nijmegen, the Canisius Wilhelmina Hospital Nijmegen, and the
Rijnstate Hospital Arnhem-Velp, The Netherlands, will be asked to participate
in this study in the period December 2015-December 2018. During the last 12
months we will finalize our database with all data and images and perform the
analyses.
The follow up period is three months.

PATIENT OUTCOME ANALYSIS The effect analysis adheres to the design of a
randomized controlled trial and measures diagnostic performance and quality of
life at baseline, and at fixed points along the follow-up of the clinical trial
(see design clinical trial). To measure the quality of the health status of the
patients a validated so-called health-related quality of life (HRQoL)
instrument will be used, the EuroQol-5D (EQ-5D) (Dolan, 1997). This HRQoL
instrument will be completed by the patients and is available in a validated
Dutch translation (Lamers et al., 2005). The EQ-5D is a generic HRQoL
instrument comprising five domains: mobility, self-care, usual activities,
pain/discomfort and anxiety/depression. The EQ-5D index is obtained by applying
predetermined weights to the five domains. This index gives a societal-based
global quantification of the patient*s health status on a scale ranging from 0
(death) to 1 (perfect health). Patients will also be asked to rate their
overall HRQoL on a visual analogue scale (EQ- 5D VAS) consisting of a vertical
line ranging from 0 (worst imaginable health status) to 100 (best imaginable).
The patient outcome analysis will be complemented with a CVM questionnaire and
measures of satisfaction and pain related to diagnosing subtype BCC.

In one group, 3 mm skin biopsies will be performed, this is the conventionale
regular diagnostic method which is invasive.
In the other group, in vivo reflectance microscopy will be performed, this is
the novel daignostic method, which is non-invasive.

The RCM-imaging itself is non-invasive, safe and painless. The 3mm punch biopsy
of the skin tumour is limited invasive, but is at present common practice in
case of suspicion on BCC. We would also perform a diagnostic biopsy if the
patient would not be included in this study. Risks of the biopsy procedure are
generally small, consisting of continued bleeding and infection. These are
generally localised and can be treated easily. In future taking biopsies may be
replaced by RCM-imaging. This could be useful for the patient himself and for
others. Skin could then be evaluated painlessly and non-invasively. Also
filling in the questionnaires may ask some time. The duration of this visit
will approximately take one hour. Treatment of a pathological proven BCC is
also normal practice, surgical excision is appropriate in these cases. Minors
and incapacitated subjects will not be included.