Clinical trial NCT03483935: Microwave Therapy for Treatment of Precancerous Actinic Keratoses
Official title: Microwave Therapy for Treatment of Precancerous Actinic Keratoses
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: NA
Conditions: Actinic Keratoses
Precancerous Skin Lesion
Lead sponsor: University of Dundee
Sponsor class: OTHER
Collaborators: name: Emblation Limited
First posted: 2018-03-30
Enrollment: 18
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Randomised, internally controlled trial
Primary purpose: TREATMENT

Brief summary: This is a two-stage feasibility study to determine if focussed microwave energy is a suitable treatment for Actinic Keratoses (AK).

The two study stages are as follows:

Stage 1:

To determine the electrical properties of permittivity in AK on the hand and bald scalp for subsequent optimisation of the SWIFT instrument to provide the correct dose of microwave energy to the AK.

Stage 2:

1. Evaluate the efficacy of microwave energy as a treatment for AK
2. Evaluate the long-term resolution of AK following microwave treatment
3. Assess the feasibility and acceptability of using microwave energy as a treatment for AK
4. Identify the potential mode of action of microwave energy in the treatment of AK.

The primary objective is to evaluate the efficacy of microwave therapy versus no treatment on the resolution of AK lesions using visual assessment. The primary outcome measure is full or partial resolution of the AK assessed by skin examination.

Detailed description: This study is a collaboration between the University of Dundee, NHS Tayside and Emblation Ltd, funded by Innovate UK. Emblation is a Scottish based Small Medium sized Enterprise (SME) and is an established global leader in the design, development and manufacture of microwave medical devices.

Actinic keratoses (AK) are believed the most common pre-cancerous lesions in humans and are precursors to invasive cutaneous squamous cell carcinoma (cSCC), a malignancy that has more than doubled in incidence in the UK in the last decade due to ageing populations and increased UV exposure (Goon 2017). The UK incidence of cSCC now exceeds 30,000 annually (estimated \>50,000 cases/year, Public Health England, unpublished data) with significant health burden and NHS costs These skin cancers are often multiple, especially in immunosuppressed high-risk populations. AK are very common "sun damage" skin lesions found on sun-exposed areas of the skin, such as the backs of hands and bald scalp. Up to 70% of our elderly population have AK and 65% of cSCC arise from previously identified AK. AK are readily identified clinically so AK treatment offers an important opportunity for cancer prevention, but our ability to treat is limited by undesirable local adverse reactions from existing topical treatments which fail to balance effectiveness, side effects and cost. None of the currently available treatments for AK are suitable for widespread use in the community and are only partially effective. Other more effective treatments such as photodynamic therapy are expensive and time consuming and need to be delivered by experts in secondary care. NHS dermatologists are already overburdened and elderly patients with AK do not wish to travel. AK therapy would be greatly improved by a cheap, convenient, well-tolerated and efficacious therapy that can be delivered closer to home by General Practitioners (GPs) or nurses.

Clinically, AK display a spectrum of severity from mild Grade 1 lesions, which are just visible and just (barely) palpable, through Grade 2 red and scaly lesions (easily felt and seen), to the most severe Grade 3 lesions, which are grossly hyperkeratotic and "thickened" skin lesions. In practice, it is easier to grade them as 'thin' (just palpable) or 'thick' (with substance to them). It is possible that the dielectric properties of Thick and Thin AK will differ and therefore the measurement study will need to be carried out on both types of AK such that the appropriate microwave dose can be given to these variable skin lesions

The investigator's hypothesis is that localised microwave energy therapy is a suitable treatment for Actinic Keratosis (AK) skin lesions.

The use of microwave technology is well established as ablative doses for treatment of malignancy e.g. hepatocellular carcinoma. There are no known studies using microwave for treatment of pre-cancerous skin conditions or skin cancers. Furthermore, there is very little understanding of the biological process evoked by localised microwave exposure in the skin or of the clinically-relevant biological mechanisms triggered.

Emblation already have a CE-marked microwave instrument used successfully for the treatment of plantar viral warts, the SWIFT device. The investigators now wish to undertake a feasibility trial in 12 participants, each with multiple AK on dorsal hand skin or bald scalp or both. The trial will examine the tolerability, acceptability, efficacy and long-term resolution of AK following one or more treatments with microwave energy delivered using the SWIFT device.

Previous studies performed by Emblation using SWIFT on plantar viral warts found it to be effective and safe. Some participants experienced minor discomfort during the microwave therapy but any pain stopped when treatment stopped. Some reddening of the skin at the treatment site may occur but this resolved after 24 hours. Some instances of a haematoma have been seen at larger doses, typically resolving within 7 days.

This will be a two-stage study, stage 1 to measure the electrical properties of AKs in patients. The data from stage 1 allows derivation of the power settings to be used with SWIFT for AK in stage 2, to conduct a randomised controlled trial of microwave treatment, delivered using SWIFT, versus no treatment.

The SWIFT device has variable power and duration controls, the protocol suitable for plantar viral warts is unlikely to be compatible with AK. Plantar warts (verrucas) are considerably thicker than AK and are located on much thicker, more robust areas of normal skin. AK are most common in the elderly population and are located on thinner, more delicate skin. The investigators therefore anticipate that AK will require a smaller dose of microwave energy than plantar warts. In order to derive the correct power and duration settings for the Swift instrument and impart the correct amount of electromagnetic energy (referred to as dose) into the AK, the dielectric properties of AK need to be determined to confirm how the specific tissue responds to the electromagnetic energy (microwave). By measuring relative permittivity (commonly abbreviated to Epsilon relative Er) the dielectric properties of the AK can be determined.

The established method of measurement requires the tissue/material under test to come into contact with a specially designed probe attached to an instrument that measures the response to a radiated signal at the same frequency (8GHz) as that used in Emblation's product "Swift". There are a number of instrument and probe manufacturers e.g. Keysight (HP/Agilent), SPEAG, Anritsu. The probe can be used to test solids, liquids and biological tissues by placing the probe in direct contact for a few seconds whilst remaining still during data acquisition by the instrument.

The instrument (Anritsu MS46122A) providing the probe excitation conforms to the following standards: CE Mark, Low voltage (2006/95/EC) and Safety (EN 61010-1:2010). The energy imparted into the lesion for the measurement will not exceed 0.5mW, by way of comparison this is far less than a mobile phone (up to 500mW) and a FitBit (1.6mW) thus there is no inherent danger to the volunteer.

Emblation employees will operate the instruments and direct the subjects to the probe. Other study team staff may work in conjunction with NHS staff at the time of recruitment and/or at the time of measurement.

Microwave energy is converted to heat in the skin layers and forms the basis of the therapy. The target temperature of 43-46 degrees Centigrade is crucial in eliciting the correct immune response in the tissue. As the current instrument is 'tuned' with an antenna for plantar warts, it may not be as efficient at imparting the energy into the AK lesions and the target temperature may not be achieved with the same power and duration settings. Conversely, if the AK provides a more efficient conversion of microwave to temperature, potentially too high a temperature may be reached at a given power and duration combination. Stage 1 data will be analysed to model the efficiency of the current antenna in computer simulations and values for input power (W) and duration (s) will be derived from the modelling data, subsequently to be used in the stage 2 of the trial. This will provide the correct dose of microwave energy to be used in Stage 2.

Once the settings required for AK have been determined, participants will be recruited into Stage 2 in order to determine efficacy, long term resolution, tolerability and potential mode of action of microwave treatment for AK.

Eligibility criteria: Inclusion Criteria:

* Male or female participants
* Age 18 years and over
* Clinical diagnosis of precancerous Actinic Keratosis made by a dermatologist
* Able to perform study assessments

Exclusion Criteria:

* Inability to give informed consent
* Implantable Cardioverter-defibrillator (ICD), pacemaker or other implantable device
* Metal implants at site of treatment
* Known allergy or intolerance to microwave therapy
* Unstable co-morbidities (cardiovascular disease, active malignancy, vasculopathy, inflammatory arthritis) which, in the opinion of the Chief Investigator (CI), would make the patient unsuitable to be enrolled in the study.
* Individuals who are immunosuppressed (organ transplant recipients, haematologic malignancies, HIV).
* Individuals will not be enrolled to the study if they are participating in the clinical phase of another interventional trial or have done so within the last 30 days. Individuals who are participating in the follow-up phase of another interventional trial, or who are enrolled in an observational study, will be co-enrolled where the CIs of each study agree that it is appropriate.

Primary outcomes:
measure: Resolution of AK Lesions Following Microwave Treatment
timeFrame: Baseline, day 8, 15, 28, 42, 60 and 120
measure: Complete Resolution of AKs Following Microwave Treatment
timeFrame: Baseline, day 8, 15, 28, 42, 60 and 120
measure: Partial Resolution of AKs Following Microwave Treatment
timeFrame: Baseline, day 8, 15, 28, 42, 60 and 120
Secondary outcomes:
measure: Level of Pain Experienced During Treatment
timeFrame: Treatment 1 (day 1) and treatment 2 (day 28)
measure: Duration of Pain Post Treatment
timeFrame: Treatment 1 (day 1) and Treatment 2 (day 28)
measure: Change in Ki67 Staining Determined Immunohistochemically by the Use of Specific Antibodies on Fixed Material
timeFrame: Day 15
measure: Change in Hematoxylin and Eosin Stain
timeFrame: Day 15 OR day 42
Other outcomes:
Locations:
city: Dundee
country: United Kingdom
facility: NHS Tayside
Study officials:
affiliation: University of Dundee
name: Charlotte Proby, MBCHB
role: PRINCIPAL_INVESTIGATOR
References:
citation: Bristow I, Lim WC, Lee A, Holbrook D, Savelyeva N, Thomson P, Webb C, Polak M, Ardern-Jones MR. Microwave therapy for cutaneous human papilloma virus infection. Eur J Dermatol. 2017 Oct 1;27(5):511-518. doi: 10.1684/ejd.2017.3086.
citation: Criscione VD, Weinstock MA, Naylor MF, Luque C, Eide MJ, Bingham SF; Department of Veteran Affairs Topical Tretinoin Chemoprevention Trial Group. Actinic keratoses: Natural history and risk of malignant transformation in the Veterans Affairs Topical Tretinoin Chemoprevention Trial. Cancer. 2009 Jun 1;115(11):2523-30. doi: 10.1002/cncr.24284.
citation: Eder J, Prillinger K, Korn A, Geroldinger A, Trautinger F. Prevalence of actinic keratosis among dermatology outpatients in Austria. Br J Dermatol. 2014 Dec;171(6):1415-21. doi: 10.1111/bjd.13132. Epub 2014 Nov 19.
citation: Goon PK, Greenberg DC, Igali L, Levell NJ. Squamous Cell Carcinoma of the Skin has More Than Doubled Over the Last Decade in the UK. Acta Derm Venereol. 2016 Aug 23;96(6):820-1. doi: 10.2340/00015555-2310. No abstract available.
citation: Liang P, Wang Y. Microwave ablation of hepatocellular carcinoma. Oncology. 2007;72 Suppl 1:124-31. doi: 10.1159/000111718. Epub 2007 Dec 13.
citation: Marks R, Rennie G, Selwood TS. Malignant transformation of solar keratoses to squamous cell carcinoma. Lancet. 1988 Apr 9;1(8589):795-7. doi: 10.1016/s0140-6736(88)91658-3.
citation: Martin R.C.G. (2011) Microwave Ablation and Hepatocellular Carcinoma. In: McMasters K. (eds) Hepatocellular Carcinoma:. Springer, New York, NY
citation: Poggi G, Tosoratti N, Montagna B, Picchi C. Microwave ablation of hepatocellular carcinoma. World J Hepatol. 2015 Nov 8;7(25):2578-89. doi: 10.4254/wjh.v7.i25.2578.
citation: Wang T, Lu XJ, Chi JC, Ding M, Zhang Y, Tang XY, Li P, Zhang L, Zhang XY, Zhai B. Microwave ablation of hepatocellular carcinoma as first-line treatment: long term outcomes and prognostic factors in 221 patients. Sci Rep. 2016 Sep 13;6:32728. doi: 10.1038/srep32728.