Review article | Published 24 December 2014, doi:10.4414/smw.2014.14026
Cite this as: Swiss Med Wkly. 2014;144:w14026
Cite this as: Swiss Med Wkly. 2014;144:w14026
Swiss clinical practice guidelines on field cancerization of the skin
a Dermatologische Klinik, UniversitätsSpital Zürich, Switzerland;b Klinik für Dermatologie/Allergologie, Kantonsspital St. Gallen, Switzerland;c Service de Dermatologie et Vénéréologie, Hôpitaux Universitaires de Genève, Switzerland; d Dermatologische Abteilung, Kantonsspital Luzern, Switzerland; e Service de Dermatologie et Vénéreologie, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland; f Universitätsklinik für Dermatologie, Inselspital Bern, Switzerland; g Dermatologie, Universitätsspital Basel, Basel, Switzerland; h Knoxville, Tennessee, USA; i Dermatologisches Ambulatorium, Stadtspital Triemli, Zürich, Switzerland; j Dermatologia, Ospedale Regionale di Bellinzona e Valli, Bellinzona, Switzerland; k Dermatologie/Allergologie, Kantonsspital Aarau, Switzerland
Summary
Abbreviations
5–FU 5–fluorouracil
AK actinic keratosis
ALA 5–aminolevulinic acid
AZA azathioprine
BCC basal cell carcinoma
CLL chronic lymphocytic leukaemia
COX-2 cyclooxygenase-2
LSRs local skin reactions
MAL methyl aminolevulinate
MMF mycophenolate
NMSC non-melanoma skin cancer
OTR organ transplant recipients
PDT photodynamic therapy
REAKT Swiss Registry of Actinic Keratosis Treatment
RCT randomised controlled trial
SA salicylic acid
SCC squamous cell carcinoma
UV ultraviolet
UVA ultraviolet-A
Actinic keratosis (AK) affects
millions of people worldwide, and its prevalence continues to increase.
AK lesions are caused by chronic ultraviolet radiation exposure, and
the presence of two or more AK lesions along with photodamage should
raise the consideration of a diagnosis of field cancerization. Effective
treatment of individual lesions as well as field cancerization is
essential for good long-term outcomes.
The Swiss Registry of Actinic
Keratosis Treatment (REAKT) Working Group has developed clinical
practice guidelines for the treatment of field cancerization in
patients who present with AK. These guidelines are intended to serve as a
resource for physicians as to the most appropriate treatment and
management of AK and field cancerization based on current evidence and
the combined practical experience of the authors. Treatment of AK and
field cancerization should be driven by consideration of relevant
patient, disease, and treatment factors, and appropriate treatment
decisions will differ from patient to patient. Prevention measures and
screening recommendations are discussed, and special considerations
related to management of immunocompromised patients are provided.
Key words: Actinic
keratosis; field cancerization of the skin; non-melanoma skin cancer;
management recommendations; clinical practice guidelines
Introduction
Actinic keratoses (AKs) are caused by
chronic ultraviolet (UV) radiation exposure. Two or more AKs on
photodamaged skin signal field cancerization and an increased risk for
invasive non-melanoma skin cancer (NMSC). Switzerland has one of the
highest rates of NMSC in Europe. Treatment of AK is thus an important
Swiss public health issue.
The Swiss Registry of Actinic
Keratosis Treatment (REAKT) Working Group (referred to herein as the
REAKT Working Group) was formed under a mandate of the Swiss Society
for Dermatology and Venereology (SGDV). The REAKT Working Group
determined that guidelines for the treatment of field cancerization in
AK were needed, as existing guidelines have focused primarily on the
treatment of discrete AK lesions. The REAKT group developed the
clinical practice guidelines herein based on available data and a
consensus of best practices in field treatment. Current and emerging
therapies were considered in order to support optimum patient care now
and as new options become available.
These guidelines present the
consensus of the REAKT Working Group regarding the desired approach to
field cancerization based on disease presentation and patient and
treatment considerations. These recommendations are not intended to be
followed rigidly, but to serve as a guide for clinical care. It must be
noted that although field cancerization is associated with other forms
of NMSC-including Bowen’s disease, squamous cell carcinoma (SCC), and
basal cell carcinoma (BCC)-these forms are outside the scope of these
guidelines for detailed discussion of treatment modalities.
About these guidelines
Methodology
The Swiss Clinical Practice
Guidelines on Field Cancerization of the Skin have been developed by an
expert panel of Swiss dermatology-oncology physicians (members of the
REAKT Working Group) to guide other dermatologists in their approach to
care for patients who have clinically apparent photodamage, AK lesions,
or field cancerization, or who are at risk for NMSC. Prof. Dr. Gunther
Hofbauer was asked to initiate the creation of the guidelines by
drafting an initial manuscript and treatment algorithm based on his
knowledge of the general treatment consensus and practice approaches of
the other members of the REAKT Working Group. All members of the REAKT
Working Group reviewed the draft manuscript and treatment algorithm in
the month of June 2013 and convened in Bern, Switzerland on 1 July
2013 to discuss and revise the guidelines. The guidelines and treatment
algorithm were revised following the meeting and the group convened
again in Bern, Switzerland in December 2013 to review and discuss the
revised guidelines. Further revisions were made and the final version
was approved on 9 March 2014.
Evidence basis
The REAKT Working Group considered
all currently available treatments for AK in the development of the
guidelines. The treatments specifically recommended within the
guidelines are those that the REAKT Working Group members agreed have
the most clinical experience, the best evidence to consider for
treatment of AK, or are of high interest currently based on factors
such as clinical trial data or mechanism of action. The recommendations
for use of each treatment are evidence-based where possible, and are
based on the quality of evidence as well as disease, patient, and
treatment considerations.
The 2011 Oxford Centre for Evidence
Based Medicine (OCEBM) Levels of Evidence (LOE) were used to
characterise the strength of the efficacy evidence for field
cancerization available for each treatment [1].
The OCEBM LOE are intended to help guide clinical decision-making.
They do not provide definitive judgment of the quality of evidence, nor
do they provide a recommendation for treatment. Clinical judgment must
be applied when considering the LOE for an individual treatment in
order to determine its appropriate use.
Disclaimers and cautions
These guidelines for treatment of
field cancerization have been prepared for dermatologists who treat
patients who have or are at risk for NMSC. The general principles that
underlie the guidelines are applicable to dermatologists in many
different regulatory environments. However, the treatment algorithm and
guidance is provided to address the specific needs of the Swiss
dermatology oncologist and it is not our intent to provide specific
recommendations that counter established practices in other countries.
In addition, these guidelines have
been developed based on the consensus of the REAKT Working Group
members as to the preferred treatment approaches based on evidence
available as of the manuscript submission date. Caution should be
exercised in interpreting our recommendations in the context of newer
data, as advances in knowledge and expansion in treatment options may
require reconsideration of these recommendations.
Finally, the intention behind the
development of the Swiss Clinical Practice Guidelines on Field
Cancerization of the Skin was to aid dermatology physicians in the
decision-making process by highlighting significant considerations that
should guide treatment and providing expert perspective on the evidence
to date on the range of treatments available for AK and associated
field cancerization. The guidelines and algorithm are not intended to
replace a physician’s best judgement on the most appropriate path for
each individual patient. The REAKT Working Group members hope that
these guidelines will support and strengthen reader decisions on
appropriate patient care.
Actinic keratosis and field cancerization background
AKs are UV light-induced discrete
intraepidermal lesions typically presenting as rough, scaly, keratotic
macules, papules or plaques. AK is an indicator of cumulative UV
exposure, and lesions typically appear on skin that has been subject to
chronic exposure--the so-called “sun terraces” of the skin, including
the face, chest, ear lobes, balding scalp, and backs of arms and hands.
Patients may present with a single lesion, but the typical clinical
presentation is multiple lesions across an area of sun-damaged skin. A
seminal Australian study of more than 1,000 people over the age of 40
found an average of 7.7 lesions per person with AK [2].
AKs are now understood as part of a disease continuum initiated by UV
radiation. Photodamage represents the earliest stage in the continuum,
with the formation of AKs, and ultimately SCC, demonstrating increasing
progression. Before invasive SCC develops, intraepithelial changes
occur in the clinical forms of AK and Bowen's disease. While only the
latter is traditionally called carcinoma in-situ due to its total loss
of regular architecture of the epidermis, we believe that AK is part of
the continuum of SCC development based on histological and molecular
changes common to AK, Bowen’s disease, and invasive SCC [3].
While we realise that not all of the community shares this strict
parlance based solely on biological parameters, for clarity's sake we
will address AK and Bowen’s disease in this paper as SCC in situ.
Histologically, AK is characterised
by atypia or dysplasia of the keratinocytes in the basal layer of the
epidermis and with progression in epidermal layers above. Disordered
maturation of the superficial layers results in alternating areas of
parakeratosis and hyperkeratosis [4]. Several histological subtypes have been described, including lichenoid, hypertrophic, bowenoid, pagetoid, and pigmented [5, 6]. Histologically, AK and SCC are indistinguishable in the epidermis [3].
A significant advance leading to more
effective treatment of AK is acceptance of field cancerization as an
underlying condition driving disease pathology and progression. UV
exposure is believed to generate field cancerization via several
actions: multiple individual foci of cellular transformation, broad
immunosuppression and reduced immunosurveillance, and additional
mutations leading to the development of invasive tumours [7].
It is widely accepted that visible AK lesions (whether few or many)
are a manifestation of pervasive damage and that the surrounding area
(“field”) of sun-damaged skin contains subclinical lesions and cellular
changes. Bowen’s disease, SCC, and BCC are also visible indicators of
this damage. The presence of any of these NMSC lesions (to include AK)
represents evidence of field cancerization.
The current focus of AK treatment is
to target field cancerization, rather than limiting treatment to
clinically apparent individual lesions. This approach may help delay or
prevent the development of new lesions [8, 9],
and is suggestive of a reduced future risk for SCC, although as yet
there is little evidence demonstrating these beneficial outcomes. It
may be helpful to envision this treatment approach as analogous to the
use of hypertensive medication to prevent endpoint events such as
stroke and myocardial infarction. Stroke and myocardial infarction are
significant events that require immediate, focused medical attention,
but treatment limited to the individual event does not adequately
promote optimum long-term outcomes. The view of AK must similarly be
broadened to understand that treatment of field cancerization should
address underlying risk factors and may promote better long-term health
outcomes and improved quality of life.
Epidemiology and risk factors
AKs occur more frequently in regions
with higher UV exposure and in fair-skinned populations. A 2006 report
from the World Health Organization noted a clear relationship between
latitude and AK prevalence as well as the likelihood of multiple AKs at
lower latitudes [10].
Prevalence rates of 40%–60% in adults in Australia and 11%–25% in
various northern hemisphere populations have been reported [11]. Prevalence rates are greater in males than in females and increase with age [11].
The most notable risk factor for
development of AK is accumulated chronic UV radiation exposure, whether
through occupational or recreational means, and the person with AK
typically presents with characteristic signs of photodamage, including
freckles and solar lentigines. Recently published results from a
multicentre study across eight European countries provides additional
information about a number of risk factors [12].
Differences in risk were noted among hair and eye coloration: red hair
conferred a seven times higher risk than black hair; brown eyes about a
40% reduced risk when compared to blue. The presence of even a few
freckles on the face was found to confer greater risk. Outdoor
occupation, history of sunburns as a child, and residency in a tropical
country were all associated with increased risk, whereas higher
education levels were associated with a significantly reduced risk. This
study also noted potentially significant increased risks in patients
taking photosensitising thiazide diuretics and cardiac drugs, and a
possible protective effect from nonsteroidal anti-inflammatory drugs
(NSAIDs).
Patients who are immunocompromised
are at significant increased risk for development of NMSC, as are
patients with genetic disorders such as xeroderma pigmentosum.
AK progression to SCC
Figure 1
Actinic keratosis and field cancerization treatment algorithm
The algorithm is intended to aid
in the treatment decision process for actinic keratosis and field
cancerization and is not intended to replace a physician’s best
judgement on the most appropriate treatment path for each individual
patient.
Although not all AKs will progress to
SCC ‒ and, indeed, some AKs will regress ‒ there is a clear
relationship between AK and SCC. A review of the evidence supporting
this relationship found that approximately 90% of SCCs may have
contiguous AKs, consistent with the concept that AKs are pre-invasive
forms of SCC [4]. One study found that up to 60% of SCCs arise directly from an AK [13].
Another study found that 136 of 165 cutaneous SCCs examined were
closely associated with AKs; of these, 26.7% of the SCCs were found to
have arisen directly from an existing AK lesion, and another 55.7% were
in close proximity to an AK lesion [14].
The proportion of AK lesions that
progress to invasive SCC is not conclusively known, with published
progression estimates ranging widely from 0.075% to 16% or even more [2, 13, 15, 16]
A recent systematic review concluded that annual rates of progression
of a single AK into SCC range from 0% to 0.53%, but cautioned that these
remain uncertain estimates [17].
A large majority of lesions remain stable and others will regress. The
review found that annual rates of regression for single lesions ranged
between 15% and 63%, with recurrence rates of 15%–53% [17]. At present, it is not possible to determine which AK lesions will progress to SCC, or regress, or when.
The uncertainty of the timing and
likelihood of AK progression has stimulated much discussion regarding
the best treatment approach to AK, with some advocating watchful
waiting and others a more aggressive approach. It is the perspective of
the REAKT Working Group that we must consider AK a serious precursor to
more invasive disease and treat promptly. Switzerland has one of the
highest skin cancer rates in Europe, with an incidence of around 15,000
new cases of NMSC each year and steadily rising [18].
Improved treatment approaches to AK as well as comprehensive public
education efforts are needed to help slow the rising incidence and
improve long-term outcomes for our population. Rigorous NMSC prevention
efforts, both individually and community-wide, may have financial
benefits. A German study of hospitalisation costs associated with
melanoma and NMSC skin cancers found that while NMSC mortality is low,
annual hospitalisation costs related to NMSC are approximately 100%
greater than with melanoma skin cancer, representing a significant
public health burden that is perhaps not well understood when viewed
solely in the context of death rates [19].
The treatment algorithm presented with these guidelines will present
the REAKT Working Group’s recommendations on appropriate treatment path
based on patient presentation and risk factors, balancing health,
fiscal, and quality-of-life concerns (fig. 1).
Prevention
As stated, chronic UV radiation
exposure is understood to play an essential role in the development of
AK and other forms of NMSC. Childhood and adolescence are pivotal
periods for prevention efforts, which should focus on reducing overall
exposure (minimising the incidence of childhood sunburn) and helping to
establish life-long self-care habits. Steadily increasing rates of NMSC
highlight the need for primary prevention measures starting in
childhood to reduce overall population-based risk for AK and NMSC.
Prevention measures focus on limiting
UVA (ultraviolet-A) photodamage through avoidance of unnecessary
exposure to UV light (including artificial sources) and the use of
sunscreen when exposure is unavoidable. A study of the sun protection
knowledge and behaviours of 887 children and adolescents (ages ranging
from 8–17 years) in Northwest Switzerland revealed that, despite wide
ranging skin cancer education and prevention campaigns, an opportunity
remains to improve child and adolescent knowledge and behaviour in this
regard [20].
The study authors identified needs for continued education about the
potential long-term effects of excessive sun exposure, proper sunscreen
application, and the effectiveness of clothing and shade as protective
measures. They also noted the need for continued efforts on changing
societal values related to tanned skin.
In adult patients, including those
who have a history of AKs or other NMSC, randomised clinical trials
have demonstrated that the use of sunscreen reduces the incidence of
AKs and SCC. A randomised, controlled trial spanning 4.5 years
demonstrated reduction in SCC (but not BCC) through the regular use of
sunscreen [21]. An eight year follow-up study evaluated the long-term effects of sunscreen application during the trial [22].
SCC rates were significantly reduced by almost 40% during the entire
follow-up period. Most of this effect was attributed to latency of
effect of sunscreen intervention during the trial. However, the study
authors also noted that the intervention group continued to use
sunscreen at a higher rate than the control group after the initial
trial. A 2009 analysis in Australia found that regular sunscreen use
was a cost-effective approach to skin cancer prevention, saving almost
US $90,000 in total healthcare costs over a 5 year period for
approximately 800 patients studied [23].
High-risk populations may also
benefit from sunscreen use. Ulrich and colleagues studied the
protective effects of regular sunscreen use on the development of NMSC
in organ transplant recipients (OTR) [24].
At the conclusion of a 24 month study, the intent-to-treat sunscreen
group had notably more favourable outcomes, with reduction in lesion
count from baseline and fewer lesions overall than the control group.
Judicious use of systemic
chemoprevention strategies may also be of benefit in very high-risk
patients. Evidence suggests that the use of acitretin may have some
benefit [25]. Two small, open-label studies demonstrated some protective benefits of oral capecitabine in OTR [26, 27].
Studies are currently underway to evaluate the efficacy of
afamelanotide, a first-in-class photoprotective drug, for use as a
photoprotective agent for OTR patients.
Actinic keratosis and field cancerization management
Table 1 outlines the REAKT Working
Group’s recommendations for screening and management of AK and field
cancerization based on patient and disease factors. Absent specific
risk factors, we recommend encouraging patients to perform skin
self-examination every 3 months, with clinical examination if new
lesions are noted. Certain risk factors require more frequent self and
clinical exams, as noted in the table. In any patient type, suspicious
lesions necessitate timely professional inspection.
Professional screening for AK and
field cancerization offers several important benefits. It enables the
patient and physician to establish a baseline (at first screening) or
note changes to the patient’s skin since the last visit, thereby
potentially promoting earlier identification of new or changing
lesions. It also offers the opportunity to evaluate for other skin
cancers, such as melanoma. Skin examinations should be comprehensive,
including areas such as the scalp, palms, oral cavity, and genitalia.
For patients at high risk for invasive skin cancer (e.g., those with
history of melanoma or who have large lesions) it is recommended that
the examination include palpation of the lymph nodes.
Clinician visits also offer the
opportunity to introduce or reinforce prevention and self-care habits,
whether through consultation or the provision of written materials.
Patients are the ultimate drivers of their care; however, they are
typically noncompliant with screening recommendations, and continued
education is needed to emphasise the importance of regular at-home
self-examination as well as clinical examination of new lesions.
Patient education on the importance of screening and the types of
changes that need to be watched versus the changes that require
immediate professional evaluation is key to a successful management
programme. As part of this education, patients should be trained on how
to effectively perform skin self-examination.
Patients with chronic lymphocytic
leukaemia (CLL) as well as OTR and other patients on long-term
immunosuppression require special consideration for screening. These
patients should be treated as at high risk for invasive NMSC. Annual
clinical exams by a dermatology specialist and monthly skin
self-examinations are encouraged for these patients; OTR should be
screened by a dermatologist for NMSC prior to transplantation [28].
The extent and, particularly, the invasiveness of skin lesions can be
clinically underestimated in OTR and patients with CLL, and lesions in
these patients should be viewed with a high degree of clinical
suspicion.
| Table 1: Management recommendations for actinic keratosis and field cancerization. | |||
| Patient presentation | Recommended management | Suggested timing | Additional information |
| Photodamage; no other risk factors | Clinical skin examination | If new lesions occur | |
| Patient-directed self-examination | Every 3 months | ||
| Fewer than five lesions; no other risk factors | Clinical skin examination | Every 12 months | |
| Patient-directed self-examination | Every 3 months | ||
| Recurrent lesions and recalcitrant lesions | Clinical skin examination | Every 3, 6, and 12 months following treatment At least every 6 months thereafter |
Recalcitrant lesion requires biopsy by dermatologist |
| Patient-directed self-examination | Every 3 months | ||
| History of skin cancer | Clinical skin examination | Every 3, 6, and 12 months following treatment At least every 12 months thereafter |
Lymph node exam by dermatology specialist in high-risk patients |
| Patient-directed self-examination | Every 3 months | ||
| CLL/OTR | Clinical skin examination by dermatology specialist | For CLL: Every 12 months For OTR: One screening exam pretransplantation Clinical exam at least every 12 months following transplantation |
Invasiveness of skin lesions can be clinically underestimated in CLL/OTR. |
| Patient-directed self-examination | Every month | ||
Clinical assessment/diagnosis
AK lesions are typically clinically
diagnosed. AK has varied presentations, but broadly presents as a
scaly, ill-defined macule, papule, or plaque, commonly flesh-coloured,
pink or reddish-brown. A classic feature of many AKs is a rough
“sandpaper” feel that is as important to diagnosis as visual
inspection. AK lesions may be solitary, but more commonly present as
multiple lesions in a photodamaged field. Clinical variants of AK have
specific distinct characteristics that must be noted for differential
diagnosis. Firm, raised lesions are at greater risk for invasive
carcinoma and should be biopsied.
Dermoscopy is very effective in
helping to diagnose AK. A prospective study of 178 patients compared
diagnostic results obtained with dermoscopy to histopathological
findings [29].
Independent blinded comparison of the results obtained through both
methods resulted in a concordance of 0.917. The sensitivity of
dermoscopy for the diagnosis of AK was 98.7%, with a specificity of
95.0%. The value of dermoscopy as a diagnostic tool is reliant on the
expertise of the physician, and recognition of the dermatoscopic
characteristics of AK lesions is necessary for accurate diagnosis. A
red pseudo-network is a widely cited characteristic dermatoscopic
finding of AK and is significantly associated with AK [30, 31].
Other features include a pattern of linear wavy vessels in facial
non-pigmented lesions and multiple gray or brown dots and globules
around the follicular ostia in pigmented lesions [30].
Dermoscopy is increasingly used to evaluate the outcomes of NMSC
treatment, and should be viewed as a helpful management tool beyond the
initial diagnosis.
Field cancerization should be
considered when multiple lesions of epithelial skin cancer (including
in situ SCC such as AK and Bowen’s disease or invasive tumours such as
SCC and BCC) occur. Moreover, chronic sun damage defined by the
presence of one or more clinical signs such as skin atrophy,
inhomogeneous pigmentation, dermatochalasis, Purpura senilis Bateman,
or Pseudocicatrices stellaires should be assessed. Once two or more
lesions of AK, Bowen’s disease, invasive SCC, or BCC with accompanying
photodamaged skin have been diagnosed in a single patient, a diagnosis
of field cancerization is warranted.
Treatment considerations
Although at this time it is not
possible to predict which AKs will progress to invasive SCC, early
diagnosis and treatment is believed to be key for minimising disease
progression and severity. It is the REAKT Working Group’s recommendation
that each patient with AK receive treatment that addresses both
visible lesions as well as the subclinical damage across the broader
field. Although not yet well documented, we believe that timely and
effective treatment of field cancerization has the potential to improve
long-term health prognosis, may reduce the economic burden associated
with treatment of more progressive disease, and may maximise cosmetic
outcomes by reducing the need for more invasive treatments associated
with more invasive skin cancers [8, 9].
Based on the patient’s presentation
and risk characteristics, the treatment strategy may differ (table 2).
Treatment success is dependent on selecting an appropriate therapy
within the context of a range of influencing disease, treatment, and
patient-specific factors. Treatment decisions must ultimately balance
efficacy, tolerability, and usage considerations. Regardless of the
treatment path selected, the goals of AK treatment remain fundamentally
the same: to clinically and histologically cure the lesions, minimise
pain and adverse events, and reduce recurrence. When working toward
these goals, clinical trial and other study data must be considered
within the context of “real world” practice. Measures of efficacy in
clinical trials include complete clearance, reduction in lesion count,
and sustained clearance rates [32].
Most studies rely exclusively on a clinical count of AKs; counts
conducted even by experienced dermatologists show marked heterogeneity [33].
Perhaps the most significant measure of efficacy is sustained
clearance of the total treatment field. Sustained field clearance
enables longer disease-free windows for patients, enhancing quality of
life and possibly reducing overall treatment burden.
Treatment decisions must also be
weighed against tolerability data and the burden presented by the
treatment regimen in the context of the patient’s disease
considerations. For example, in a patient with no known risk factors and
a single clinical lesion the treatment path may appropriately be quite
different from that of the patient with many visible lesions in a
damaged field and a history of prior NMSC. Lesion location is an
important factor, as lesions located in difficult-to-treat areas (e.g.,
the back) may prove too burdensome for patient-directed home-based
treatment. The treatment algorithm we provide herein as a guide to
treatment decisions provides different general paths dependent on the
patient’s disease severity and unique risk profile. Ultimately, your
professional judgement of what is best for your patient should drive
your final decision.
Specific considerations related to
the patient’s lifestyle, competence, and attitude toward treatment
should significantly influence the treatment decision, as they are all
important contributors to the patient’s adherence behaviours. Patient
nonadherence to therapy is a pervasive problem in healthcare and is a
complex issue influenced by many social, economic, disease, patient,
and treatment factors [34].
Because treatment adherence is the foundation of good outcomes, it is
essential to anticipate common factors associated with poor adherence
and effectively work to overcome patient barriers. Some barriers to
treatment adherence are somewhat easier to overcome by choosing
therapeutic regimens that are less complex or those that better reflect
patient preferences for administration or vehicle, as appropriate.
Other barriers are more difficult, such as sustained commitment
required for certain treatment plans. A treatment path must be selected
that considers the patient’s ability and willingness to adhere to
therapy, and in some circumstances these factors will outweigh the
other considerations in favour of a particular therapy. For example,
certain treatments are physician directed by design and may be
appropriate choices for patients that you believe may be less adherent
to therapy because of such issues as health, lesion location, or
willingness to adhere to long-term therapeutic regimens. Topical
therapies are typically patient driven and thus may be more convenient
for patients who are able to manage their own treatment. However, many
topical therapies require longer-term treatment administration of
several weeks or more, which raises the possibility of poor adherence
attributable to treatment fatigue and dissatisfaction due to side
effects.
| Table 2: Factors that influence treatment decisions for actinic keratosis and field cancerization. |
| Disease-specific factors |
| Progression/development of disease |
| Number of lesions |
| Localisation and severity of disease |
| Location of lesions |
| Recurrence |
| Patient-specific factors |
| Age |
| Mental condition |
| Ability and willingness to adhere to therapy |
| History of skin cancer |
| Risk factors, especially immunosuppression |
Treatment options
Figures 2A, 2B, 2C:
Summary of treatment-related considerations for actinic keratosis and field cancerization
Treatments have been assessed
according to the subjective opinions of the authors based on their
collective practical experiences and not necessarily supported by
objective data. Treatments are listed in alphabetical order. It is not
the intention of the REAKT Working Group to preferentially promote the
use of one modality or product over another.
Treatment approaches to AK can be
broadly divided into lesion-directed or field-directed. Lesion-directed
therapies work by physically destroying individual clinically apparent
lesions and are best reserved for use in patients who have only a few
isolated lesions and no elevated risk for development of invasive NMSC.
Field-directed therapies target both clinically visible lesions as well
as preclinical lesions and other changes in keratinocytes in the skin
surrounding the visible lesion. Because AK is a visible marker of more
extensive damage caused by chronic UV radiation exposure, the REAKT
Working Group recommends field-directed therapy as the optimal
treatment approach for most patients.
As discussed in more detail below,
each treatment option has a unique profile. We do encourage the use of
treatments that have shown greater efficacy in treating field
cancerization; however, it is not the intention of the REAKT Working
Group to preferentially promote the use of one modality or product over
another, except within the context of specific patient or disease
factors. It should be noted that we considered the body of evidence
available for each treatment when assessing the treatment’s efficacy
and when making recommendations for each treatment’s best use. Clinical
characteristics of AKs vary from study to study and the reader should
be aware that efficacy rates are not comparable in a head-to-head
manner because of differences in disease presentation, patient
characteristics, and study design, among other factors. Despite these
inherent limitations, the body of evidence does allow us to conclude
that there are a number of safe and effective treatment approaches, and
efficacy rates among various treatments largely overlap [36]. Each physician should select the approach that works best for each patient’s needs. Fig. 1
presents a visual guide designed to assist physicians with the
important decision points inherent to determining the best treatment
approach for each individual patient.
Sunscreen
Several studies have demonstrated
benefit with regular sunscreen use for prevention of new AK lesions and
mitigation of field cancerization progression to SCC and other
invasive skin cancers [21, 24, 37, 38].
One randomised, placebo-controlled study (n = 588) in Australia also
examined AK lesion remission rates from daily sunscreen use [38].
In this study, the group using sunblock (broad spectrum, SPF 17) had
more lesion remissions than in the control group (OR = 1.53; 95% CI,
1.29–1.80). The authors noted a clear dose-response relationship that
applied to both the formation of new lesions and remission of existing
lesions.
It is clear that sunscreen use offers
some benefit to patients with field cancerization, probably by
removing the tumour promotion via UV light. Because of this benefit and
low barriers to sunscreen’s use, we recommend that all patients
presenting with field cancerization be encouraged to use sunscreen
frequently (daily is recommended). Education is recommended to ensure
that patients use an appropriate dose; under-dosing is a common
mistake.
Curettage
Curettage is not a first-line therapy
for treatment of AKs; however, some clinicians still advocate its use,
as it is a quick and effective method for clearing visible, discrete
lesions. The treatment requires local anaesthesia and is best reserved
for treating a small number of AKs and/or thick, hyperkeratotic
lesions. Curettage is commonly followed by electrodessication to destroy
any remaining abnormal tissue and to reduce bleeding. Any potential
benefits of curettage must be balanced against common adverse outcomes,
including infection, scarring, and pigmentary changes. Curettage has
no benefit in treating subclinical lesions or the broader damaged
field.
Cryotherapy
Cryotherapy is the most widely used
nonsurgical technique for treatment of a broad range of skin cancers
and remains the most common treatment for AKs [39].
It is procedurally simple, widely available in both specialist and
generalist offices, and is a quick and effective approach to clinically
apparent lesions. Despite its popularity as a treatment, few studies
have attempted to determine the true efficacy of cryotherapy in
practice, and there is no standardised approach to frequency, duration,
intensity, or temperature of cryotherapy. This leads to a variety of
physician-specific approaches with resulting differences in outcomes.
A prospective, multicentre study of
90 patients in Australia recruited expert physicians and allowed them
to treat each patient using the freeze time they felt was appropriate
and adequate based on their clinical experience [40].
Results from this study revealed a broad range of freeze times (from 2
s to 1 min 30 s) and complete response rates (on the face and scalp)
from 39% for treatment durations shorter than 5 seconds to 83% for
treatments in excess of 20 seconds. The study authors noted that the
cure rates obtained by these expert physicians were as a whole much
lower than previously reported cure rates with cryotherapy. In general,
higher efficacy rates were linked to longer freeze times; longer
freeze times, in turn, were associated with higher incidence of
undesirable adverse effects. Cosmetic response was rated “good” or
“excellent” in 94% of the patients who had a 100% response rate at 3
months following treatment. Hypopigmentation was noted in 29% of the
complete response lesions.
In a study of the comparative safety
and efficacy of methyl aminolevulinate (MAL)-photodynamic therapy (PDT)
versus cryotherapy as treatment of AKs on the extremities of 121
patients, the complete response rate for cryotherapy at 24 weeks was 88%
[41].
The cosmetic outcome was assessed as “excellent” in 56% of patients who
received cryotherapy. A randomised comparative study of imiquimod 5%,
5–fluorouracil (5–FU), and cryotherapy for treatment of AKs in 75
patients documented initial and 12 month clearance rates for each
therapy [42].
Cryotherapy was associated with a 68% initial clearance rate, a 32%
histological clearance rate, and 12 month sustained clearance rate for
initially cleared lesions of 28%. This study also measured sustained
clearance across the total treatment field; the sustained field
clearance rate for cryotherapy was 4%.
A recent meta-analysis of complete
clearance rates associated with eight common interventions for AK
(including common topical treatments and PDT) found that the efficacy
outcomes from cryotherapy were superior only to diclofenac and placebo [43].
The authors did note that the analysis may have tended to favour
field-directed treatments over those that were lesion-directed.
Pain, redness, oedema and blistering
are common side effects of treatment with cryotherapy. In addition,
significant local adverse events, such as hyper- or hypopigmentation,
scarring, and hair loss have been observed [40, 44].
Cryopeeling (diffuse cryotherapy) has
been suggested as a possible approach for treating individual AKs as
well as the broader damaged field [45].
Evidence for this treatment is limited, and no standardisation in
approach or methods exists. More effective and well-tested options are
available.
5–Fluorouracil
Topical 5–FU has a long history in
dermatology and has been extensively used as treatment for AK. The drug
interferes with deoxyribonucleic (DNA) and ribonucleic (RNA) synthesis
in rapidly dividing cells, preventing cell proliferation and resulting
in cell death. Clinical study of 5–FU has reported field clearance
rates of 42% to 96%, with recurrence rates up to 55% [42, 46, 47].
5–FU is associated with an almost
100% incidence of local skin reactions. Currently, a 5% formulation of
fluorouracil is available in Switzerland for treatment of senile and
actinic keratosis, requiring application once or twice daily for 3–4
weeks, or longer in some cases. A 0.5% fluorouracil formulation, not yet
available in Switzerland, has demonstrated similar efficacy rates as
the 5% formulation, but appears to cause less severe adverse events and
is associated with improved patient satisfaction [47–49].
A recent meta-analysis of complete clearance rates ranked both the 5%
and 0.5% formulations of 5–FU as superior to the other interventions
evaluated, including common topical treatments, PDT and cryotherapy [43].
These results should be interpreted with caution as the definition of
the efficacy outcome “complete clearance” varied between the studies
included in the analysis.
A combination product of 5–FU 0.5%
plus salicylic acid (SA) 10% solution is approved in Switzerland for
once-daily application, with clinical trial data available for
experiences over 12 weeks of therapy. A randomised multicentre study
compared the combination product to the study drug vehicle and
diclofenac 3% [50].
Patients treated with the combination 5–FU + SA demonstrated
significantly greater histological clearance (72%) and complete
clearance (55.4%) rates at 20 weeks than either the vehicle or
diclofenac. Application-site reactions were more common with the 5–FU +
SA product, but were mostly mild to moderate.
Diclofenac
Diclofenac sodium 3% gel in a
hyaluronic acid vehicle is approved in Switzerland for treatment of AK
with a twice-daily administration for 60–90 days. Diclofenac is a
nonsteroidal anti-inflammatory cyclooxygenase-2 (COX-2) inhibitor.
Activation of COX-2 has been implicated in UV-induced skin cancers;
inhibition of the COX-2 pathway has been shown to significantly reduce
UV-induced tumourigenesis [51].
Diclofenac sodium 3% gel in hyaluronic acid also induces apoptosis,
which is believed to play an important role in its effectiveness as an
AK treatment [52].
Phase 3 studies of topical treatment
with diclofenac demonstrated complete clearance rates of 33% following
60 days of treatment[53] and 50% following 90 days of treatment (clearance was assessed 30 days post-treatment in both studies) [54]. A 2005 meta-analysis of three randomised trials reported an overall complete clearance rate of 40% (364 patients) [55].
A phase 4 open-label study of diclofenac in patients with five or more
AK lesions demonstrated similar results, with 41% complete clearance
at day 90 of treatment and 58% at the 30–day follow-up visit [56].
A 12 month extension from this study demonstrated 79% complete
clearance of target lesions and 30% for cumulative lesions
approximately 1 year post-treatment [57]. Diclofenac is typically associated with mild-to-moderate application-site reactions.
The results of one case series [58] and a randomised controlled trial [59]
suggest that diclofenac sodium 3% gel is effective and well tolerated
as a treatment of AKs in OTR. The complete clearance rate in the
randomised controlled trial was 41% and overall lesion counts
decreased; importantly in this high-risk patient group, there were no
cases of invasive SCC or aggressive AK in the 24 month follow-up period
[59].
Imiquimod
Imiquimod is an immune-response
modifier that is well studied for treatment of AK. It is approved in
Switzerland for treatment of clinically typical, nonhyperkeratotic,
nonhypertrophic AKs on the face or scalp. The approved course of therapy
is 3 times per week for 16 weeks. Complete clearance rates from
clinical trials of this protocol range from 48.3% to 57.1% [60, 61].
Long-term follow-up data from four phase 3 clinical trials in the US
and Canada revealed that 24.7% of patients who applied imiquimod three
times weekly had a recurrence of AK in the original treatment area
after a median follow-up period of 16 months [62].
Several studies have evaluated the
safety and efficacy of a 4 week treatment protocol. In one
vehicle-controlled, randomised, double-blind study, complete clearance
rates were 26.8% after the first cycle (4 weeks) and 53.7% overall
following a second cycle in patients with lesions remaining after the
first cycle [63].
The 12–month sustained clearance rate was 61%. Another study showed
similar results with an overall complete clearance rate of 55% [64].
Topical imiquimod causes local skin
reactions (LSRs), including severe erythema, scabbing, and ulceration.
In addition, it has been associated with fairly significant adverse
events, including rare reports that in some patients its use caused
flares of previously controlled auto-immune diseases [65–68]. Despite these potential side effects, imiquimod is typically well tolerated.
In 2012, a 3.75% imiquimod
formulation was approved in Europe. Clinical trial data demonstrates
high clearance rates and potentially improved patient tolerance with the
lower concentration. Imiquimod was tested in two concentrations ‒
2.5% and 3.75% ‒ applied daily to the full face or scalp in a 2/2/2
protocol (treatment daily for 2 weeks, followed by 2 weeks without
treatment, and then another 2 weeks with daily treatment) [69].
The complete clearance rate associated with imiquimod 3.75% 2/2/2
administration was 35.6% and the partial clearance rate was 59.4% [69].
Two additional placebo-controlled trials evaluated a 3/3/3 regimen
(treatment daily for 3 weeks, followed by 3 weeks without treatment,
and then another 3 weeks with daily treatment) with imiquimod 2.5% and
3.75%, with similar results [70].
Although most subjects experienced LSRs (up to 55% of which were
considered severe in the 3/3/3 protocol group), patient adherence rates
exceeded 90% in the trials [69, 70].
Resiquimod (emerging therapy)
Resiquimod is an investigational
toll-like receptor 7 and 8 antagonist currently in phase 3 trials in
Switzerland for treatment of AK. Resiquimod’s immunomodulatory effects
are comparable to imiquimod, but it has greater potency in inducing
cytokine expression [71, 72].
A phase 2 dose-ranging study evaluated the safety and efficacy of
four different concentrations of resiquimod gel (0.01%, 0.03%, 0.06%,
and 0.1%), applied once daily three times per week for four weeks [73].
Studied patients had 4 to 8 AK lesions on the face or balding scalp.
Complete clearance rates after one course of treatment ranged from 40%
(0.01% concentration) to 74.2% (0.03% concentration). After an eight
week treatment-free interval, patients with remaining lesions received a
second course of treatment. Overall complete clearance rates ranged
from 77.1% (0.01% concentration) to 90.3% (0.03% concentration). The
most common adverse events were application-site reactions. In the
dose-ranging study higher concentrations were associated with a greater
incidence of adverse events and more severe adverse events. The lower
concentrations (0.01% and 0.03%) were better tolerated.
Ingenol mebutate
Ingenol mebutate is the most recent
entry to the AK treatment armamentarium. It has been available for use
in the US and European Union since 2012, and was approved in
Switzerland in June 2013 for treatment of nonhyperkeratotic,
nonhypertrophic AKs. Ingenol mebutate is a novel drug that appears to
have two distinct and complementary mechanisms of action: initial rapid
lesion necrosis within hours of application followed by specific
neutrophil-mediated, antibody-dependent cellular cytotoxicity within
days [74].
Ingenol mebutate gel is available in
two strengths: 150 mcg/g, administered once daily for 3 consecutive
days to the face and/or scalp; 500 mcg/g, administered once daily for 2
consecutive days to the trunk and/or extremities. A pooled analysis of
2 phase 3 studies of ingenol mebutate 150 mcg/g for the face/scalp
indicated that ingenol mebutate is significantly more effective than
placebo, with a complete clearance rate of 42.2% versus 3.7% for
placebo (p <0 .001="" a="" href="http://www.smw.ch/content/smw-2014-14026/#REF35">35
].
A pooled analysis of 2 additional phase 3 studies of the 500 mcg/g
concentration for the trunk/extremities revealed similar efficacy, with
a complete clearance rate of 34.1% with ingenol mebutate versus 4.7%
with placebo (p <0 .001="" a="" href="http://www.smw.ch/content/smw-2014-14026/#REF35">35].
LSRs were the most common adverse events in the phase 3 studies [35].
For the 150 mcg/g concentration, LSRs peaked at day 4 following
treatment initiation, rapidly decreased by day 8, and then continued to
decrease until returning to baseline around day 29. For the 500 mcg/g
concentration, LSRs peaked between days 3 and 8, and then followed a
similar pattern as with the 150 mcg/g concentration, returning to
baseline by about day 29. Fewer than 2% of subjects who received
ingenol mebutate experienced more serious adverse events. More than 98%
of patients in the 4 trials completed the treatment protocol, thus
showing adherence rates similar to those expected with
physician-directed treatments [35].
A total of 171 patients who had
achieved complete clearance by day 57 in the ingenol mebutate phase 3
trials completed a 12 month observational follow-up study [75].
The patients were seen at 3, 6, 9, and 12 months following their
day-57 visit from their original study. During each visit the target
treatment area was evaluated for presence of AK lesions, and total
lesions were counted. The primary endpoint was recurrence of AK in the
target treatment area, with an additional endpoint of the percentage
reduction in total AK lesions from the patient’s original baseline in
their original study. At 12 months, there was a 46% sustained clearance
rate (face and scalp lesions) and an 87% reduction in the number of AK
lesions compared to baseline.
A pharmacokinetic study investigated
the potential for systemic absorption of ingenol mebutate and two of
its metabolites following topical administration of ingenol mebutate
gel [76]. Approximately 1 gram of ingenol mebutate gel 0.05% was applied once daily for two consecutive days to a contiguous 100 cm2
treatment area on the dorsal forearm of 13 patients; 3 patients
received vehicle gel in identical administration. All patients had
multiple AK lesions in the treated area. Whole blood samples were taken
pre-dose on days 1 and 2, and 7 additional samples were taken in the
24 hours following the day-2 dose. No systemic exposure of ingenol
mebutate or its metabolites was detected in any sample (lower limit of
quantification = 0.1 ng/mL).
Photodynamic therapy
PDT involves the irradiation of AK
lesions with light to cause cell death. Prior to light exposure, a
photosensitising agent is applied; neoplastic cells accumulate more of
the agent than normal cells and are thus subject to greater thermal and
chemical effects. The most frequently used photosensitising agents are
5–aminolevulinic acid (ALA) and its methyl ester MAL. MAL-PDT is
approved in Switzerland for treatment of thin or nonhyperkeratotic AKs
on the face or scalp. ALA-PDT is approved for treatment of mild AKs
with a maximum diameter of 1.8 cm on the face and hairless regions of
the scalp. In addition to topical creams, an ALA patch is also
available and demonstrates similar efficacy as the creams. Treatment
protocols for PDT are not yet standardised; incubation times,
wavelength, and dose differ in both trial and practice. Recent efforts
have been made to issue guidelines to help clarify the most successful
approaches for various dermatology conditions, including AK and field
cancerization [77–81].
Studies of ALA-PDT and MAL-PDT reveal
similar efficacy. One study of ALA-PDT demonstrated 66% lesion
clearance at 8 weeks (following single treatment) and 85% at 16 weeks
(following retreatment) [82]. Another study of ALA-PDT demonstrated complete clearance rates of 66% at week 8 and 73% at week 12 [83]. A study of MAL-PDT demonstrated complete (lesion) response rates of up to 89% with retreatment [84].
Pretreatment curettage is often used in conjunction with PDT and
probably enhances the efficacy rates. PDT is associated with pain (more
significant with ALA) and hypersensitivity to light. However, PDT can
be used over large areas in a single session and has been associated
with favorable cosmetic results. A recent study demonstrated that
MAL-PDT was associated with reduced keratinocyte atypia on photodamaged
skin (supporting its efficacy in field cancerization) as well as an
increase of new collagen deposition (perhaps explaining its beneficial
cosmetic effect) [85].
In patients with thin AK lesions in
large field-cancerized areas, daylight-mediated PDT may provide an
effective and less painful treatment option [86].
Several small randomised clinical studies of daylight-mediated PDT for
treatment of mostly thin AK lesions on the face and scalp have
demonstrated 3–month lesion response rates of 75%–79%, with
significantly less pain than reported with conventional PDT [87–89]. This treatment approach is still in development.
Radiotherapy
Radiotherapy (or radiation therapy)
is an effective approach for treatment of AK and field cancerization in
patients who require treatment of a large field with a multiplicity of
lesions [90–92].
In addition, physicians have reported excellent results using
radiotherapy in patients with lesions that have not been responsive to
other treatments [90, 91].
Radiotherapy allows irradiation of
large fields (the size of two outstretched hands) of damaged skin at
each session, and is most commonly used for treatment of the face and
balding scalp. Recommended treatment is six sessions over three weeks,
although some case reports have reported more sessions [91].
Cosmetic outcomes are typically excellent, and effects of treatment
last up to two decades. Radiotherapy treatment for cutaneous neoplasms
on the trunk and limbs has been associated with poorer cosmetic
outcomes [93], but radiotherapy may be used to treat the lower arms and legs if indicated.
Grenz ray therapy is the preferred
modality, as soft X-ray therapy may induce permanent alopecia. Side
effects and adverse events are typically limited to some mild
discomfort and reddening of the skin for two weeks following the
treatment. Because there is a small increased risk for development of a
secondary malignancy due to treatment, radiotherapy is contraindicated
for treatment of AK in immunosuppressed patients. In addition,
radiotherapy is best reserved for older patients (60 years +) in order
to maximise the typically long-term results of treatment while
minimising the risk for secondary malignancy, which also has a
typically long-term latency period.
Other therapies
Other treatments for AK are
available, but the evidence behind their use is less robust in
comparison to effective options already presented. We briefly review
these other treatment options and their potential place in the current
armamentarium.
Excision of AK lesions is not a
first-line treatment approach. Shave or punch excision is occasionally
used to treat individual lesions, typically to obtain a specimen for
histologic examination in cases of suspected invasive SCC [94].
A multicentre, hospital-based case-control study of dermatology
departments in eight European countries obtained information about
physician treatment preferences for skin cancer and found that surgical
approaches were the most common choice for the treatment of most
tumours, with a notable exception in the treatment of AK, where
nonsurgical treatment was recommended in 91.4% of cases [39]
Skin grafting may have some benefit
in high-risk patients. A retrospective study of eleven kidney
transplant patients who underwent surgical resurfacing of the entire
dorsum of the hand as a treatment for multiple skin cancers
demonstrated no recurrences of skin cancer over a mean follow-up time
of 4.7 years [95].
Cosmetic appearance was acceptable. The study authors suggested this
surgical approach as a possible prophylactic treatment in patients with
severely actinically damaged skin.
Topical retinoids have been studied
for treatment of AK, but are seldom used by contemporary physicians.
Results from a few studies indicate some limited benefit compared to
placebo; however, recent results from a large randomised chemoprevention
trial in high-risk patients demonstrated no differences in NMSC
development or AK counts between the tretinoin group and the control
group [96].
Skin resurfacing with chemical peels
or lasers has shown some good results. A small, randomised, prospective
study comparing carbon dioxide (CO2) laser resurfacing, 30%
trichloroacetic acid (TCA) peels, and 5–FU administration (3 weeks)
demonstrated similar efficacy results among the three treatment groups [97].
The efficacy of chemical peels is dependent on the agent used, and
reported efficacy rates vary. Similarly, reported efficacy results from
laser resurfacing have varied, as these results are highly dependent
on the skill and technique of the treating physician. More study of the
optimum approach is required to assess where laser may fit into the AK
treatment armamentarium.
Small studies have reported some
benefits from dermabrasion for treatment of AK. However, these study
results are not compelling. In addition, dermabrasion requires local
anaesthesia and has the potential for significant side effects,
including bleeding and scarring.
Table 3 summarises the available
treatments for AK discussed throughout this section and their efficacy
in the treatment of field cancerization. Fig. 2
presents the REAKT Working Group’s assessment of each available
treatment within the context of important considerations related to
selecting the optimum treatment for specific patients.
| Table 3: Summary of treatments for actinic keratosis and efficacy in the treatment of field cancerization. | ||||
| Treatment | LD/FD | Efficacy in treatment of field cancerization | Comments | |
| Evidence of treatment benefits | OCEBM LOE | |||
| Sunscreen | FD | Use of sunscreen improves lesion remission and reduces lesion progression. | 2 | Use is encouraged adjunctively for all patients. May be used as sole treatment in some patients. Should be applied to all sun-exposed areas. |
| Curettage/ electrodessication | LD | Undocumented | N/A | May be beneficial in hyperkeratotic lesions and in combination with field therapy. Localised use preferred over field application. |
| Cryotherapy | LD | Some field cancerization benefit reported in a review of charts from a single practice where patients were treated with a cryopeeling technique. | 4 | Widely used lesion-directed treatment. Physician-directed treatment. Approach is not standardised, leading to wide range of outcomes. Localised use preferred over field application. |
| 5–Fluorouracil | FD | Complete clearance rates for 5% 5–FU: • 42%-96%, 4 weeks post treatment • Sustained clearance rate at 12 months: 33% (one RCT) Complete clearance rate for 0.5% 5–FU + SA at 8 weeks following treatment: 55.4% |
1 | Treatment of large areas possible with occlusion (Unna boot). This use is physician directed. |
| Diclofenac | FD | Complete clearance rate 30 days following treatment: approximately 40% (meta-analysis of 3 RCTs with treatment duration either 60 or 90 days) | 1 | Good cosmesis. Larger areas can be treated depending on side effects and patient tolerance. |
| Imiquimod | FD | Complete clearance rates after 16 week course: 48.3% to 57.1% Complete clearance rates after 4 week short course treatment: 26.8% after one course; 53.7% after two courses |
1 | Unmasking of subclinical lesions. Systemic reactions rarely. Larger areas can be treated depending on side effects and patient tolerance. |
| Resiquimod (currently in Phase 3) | FD | Complete clearance rates 8 weeks following treatment: • After one course of treatment: 40% to 74.2% (dose dependent) After second course of treatment: 77.1% to 90.3% (dose dependent) |
3 | Treatment aimed at biological response (inflammation). Inflammation may be early or late. Larger areas can be treated depending on side effects and patient tolerance. |
| Ingenol mebutate | FD | Complete clearance rates 57 days following treatment: • 37%-47% (face) • 28%-42% (body) Sustained clearance rates at 12 months following treatment (patients who had achieved complete clearance at 57 days): • 46.1% (face) • 44% (body) |
1 | Strong local reaction with short administration time. Larger areas can be treated depending on side effects and patient tolerance. |
| Topical retinoids | FD | Varied efficacies reported. Recent RCT reported no observed difference in lesion counts between topical tretinoin and placebo. | 2 | Not recommended due to low efficacy. |
| ALA/MAL + PDT | LD and FD | Lesion clearance rates range from 66% to 89% depending on photosynthesising agent and treatment regimen. Small studies indicate benefit for treatment of field cancerization. | 3 | Physician-directed treatment. Pain is a consideration, and will limit the size of treatment field depending on patient preference and previous experience. Daylight PDT in development. |
| Radiotherapy (Grenz ray) | FD | 13 out of 16 patients had complete clearance 2 weeks following treatment completion. | 4 | Physician-directed treatment. Recommended that its use be limited to patients over 60 years of age. 1 treatment cycle per field per lifetime. Grenz ray is recommended. Soft X-ray may induce alopecia. Larger areas can be treated depending on side effects and patient tolerance. |
| Excision | LD | Undocumented | N/A | Not a first-line treatment. Appropriate only for localised use. Typically reserved for lesions highly suspicious for invasive SCC. |
| Skin grafting | FD | 11 out of 11 patients had complete clearance out to 4.7 years. | 4 | Rarely used; may be helpful in singular cases involving areas of pronounced field cancerization, such as the back of the hands. |
| Chemical peels | FD | AK lesion reduction of up to 89% reported. | 3 | May be helpful in select patients. Larger areas can be treated depending on side effects and patient tolerance. |
| Laser | FD | AK lesion reduction of up to 92% reported. | 3 | May be helpful in select patients. Larger areas can be treated depending on side effects and patient tolerance. |
| Dermabrasion | FD | Some sustained benefit observed in small case series. | 4 | May be helpful in select patients. Larger areas can be treated depending on side effects and patient tolerance. |
| Note: The level of evidence has been noted based on evidence of each treatment’s efficacy for field cancerization. Treatment comments and recommendations for use are based on a consideration of available evidence as of the article submission date regarding treatment of field cancerization, in conjunction with the subjective opinions of the authors based on their collective practical experiences. It is not the intention of the REAKT Working Group to preferentially promote the use of one modality or product over another except within the context of evidence and experience that supports better efficacy for a patient’s unique presentation. | ||||
Combination therapy: concomitant and sequential approaches
Combination therapy is appropriate for
most patients with AK, and may be especially helpful when treating
patients with many lesions. Although lesion-directed therapy is not
recommended for treatment of field cancerization, judicious use of
lesion-directed therapy in combination with field-directed therapy may
prove to the most beneficial approach in some patients. Combining the
use of two or more modalities or complementary topical agents has
several theoretical advantages, including the possibility of enhanced
therapeutic effect and improved utility in recalcitrant disease.
Although the potential benefits of combination therapy are significant,
there is much to learn about optimum approaches. The body of evidence
in support of combination therapy is growing, but is currently sparse.
Lack of guidelines or standardised treatment protocols for use of
various modalities or topical agents in combination also hampers
efforts to identify the most useful combinations in practice. The myriad
possible combinations also present added risks for synergistic adverse
events, with potential for increased treatment-related pain and LSRs.
PDT in combination
One study of 24 patients demonstrated
greater efficacy resulting from sequential therapy with ALA-PDT +
imiquimod 5% versus ALA-PDT + placebo [98].
A randomised pilot study compared the use of MAL-PDT monotherapy,
imiquimod 5% monotherapy, and sequential therapy with MAL-PDT +
imiquimod 5% in patients with AK on the face and scalp [99].
Sequential therapy provided a better response than either therapy
alone, with “significantly less intense local reactions” and greater
patient satisfaction than imiquimod 5% monotherapy [99].
Studies have also investigated
sequential treatment strategies using topicals as the initial therapy,
followed by PDT. A small controlled study indicated that pretreatment
with tazarotene may enhance the effects of ALA-PDT across the entire
treatment field [100]. A prospective case-based assessment of sequential application of 5% 5–FU + PDT indicated enhanced results over PDT alone [101].
A randomised, placebo-controlled, double-blind pilot study of 10
patients investigated whether pretreatment with diclofenac would
improve the results obtained from PDT [102].
Pretreatment with diclofenac was found to significantly reduce lesion
count at 12 months, but was associated with more pain during PDT.
Cryotherapy in combination
A number of studies have investigated
the use of cryotherapy in combination with other therapies. In one
randomised, double-blind, placebo-controlled study, patients with AK
were treated with cryotherapy followed by application of imiquimod
3.75% or placebo cream daily for two 2–week cycles [103].
The results demonstrated that the use of imiquimod 3.75%
post-cryotherapy resulted in subject complete clearance rates of 60%
versus 30% in subjects who received placebo (p <0 .001="" 12="" 5="" a="" ak="" although="" an="" and="" clearance="" combination="" combined="" counts="" efficacy="" for="" found="" href="http://www.smw.ch/content/smw-2014-14026/#REF104" imiquimod="" improved="" in="" lesion="" of="" open-label="" postcryotherapy="" regard="" similar="" study="" target="" the="" therapy="" to="" tolerated.="" vehicle="" versus="" was="" week="" well="" with="">104
].
Similarly, the results of an
open-label phase 4 study of 714 enrolled patients found that
cryotherapy followed by application of diclofenac for 90 days was
significantly more effective at clearing lesions than cryotherapy
alone: 64% achieved complete clearance with sequential therapy versus
32% with cryotherapy alone [105].
However, more patients assigned to sequential therapy discontinued
treatment because of adverse events. A small case series of patients
who received diclofenac gel for 12 weeks followed by cryotherapy when
needed for recalcitrant lesions demonstrated a substantial reduction in
lesion count and a mean lesion-free period of 10 months [106]. No treatment discontinuations due to adverse events were noted.
A randomised controlled trial of the
effect of treatment with 0.5% 5-FU followed by cryotherapy to residual
lesions at 4 weeks following treatment initiation found that the
combination was significantly more effective in lowering 6 month lesion
count when compared to cryotherapy alone [107].
A phase 3 study is currently in
progress comparing the safety and efficacy of a sequential treatment
regimen of cryotherapy followed by field treatment with ingenol mebutate
gel 0.015% versus cryotherapy followed by vehicle gel for treatment of
AKs on the face and scalp [108].
Complete clearance rates at 11 weeks following sequential treatment
with cryotherapy + ingenol mebutate were significantly higher than the
rates observed with cryotherapy + vehicle gel (60.5% vs 49.4%; p =
0.04) [109]. Adverse events and LSRs were comparable to those observed in other studies.
Combining topical therapies
Combinations of topical therapies may
also be beneficial. One study of 64 patients tested the combination of
two established topicals, imiquimod 5% and 5–FU [110].
48 patients completed the study and achieved clearance of their AKs
after 3 treatment cycles; the combination was judged to be relatively
faster and more convenient than either therapy alone. A case-control
study of 10 patients confirmed the potential efficacy of this
combination in patients with treatment-refractory AK [111].
As the therapeutic armamentarium for
AK continues to expand, targeted combination treatment plans will
likely play a larger role in treating AKs and field cancerization.
However, more evidence is needed to determine the combinations that
provide the best balance of efficacy and safety in practice.
Management considerations for the immunocompromised
Patients who are immunocompromised
require diligent monitoring for AKs and other NMSC and aggressive
treatment if lesions are noted. Patients with CLL are at significant
elevated risk for development of cutaneous neoplasms; multiple
instances or aggressive forms of skin cancer could raise suspicion of
CLL.
OTR are an important and growing
subset of patients at increased risk for the development of NMSC.
Advances in organ transplantation management have increased the
survival time of OTR to 20 years or more following transplantation [112].
OTR are subject to the same risk factors as the general population,
but with the added burden of immunosuppressive therapy. It has been
estimated that up to 40% of OTR patients develop pre-malignant tumours
within the first five years of immunosuppression [112, 113]. OTR also bear increased risk for developing lesions with unusual presentation and aggressive progression rates.
A Swiss study of 243 renal transplant
recipients on immunosuppressive therapy confirmed an increased risk
for the development of AKs and NMSC, especially SCC (ratio of BCC: SCC
was 1:7) [114].
Older age, male sex, and fair skin were factors associated with higher
risk for developing AKs and/or SCC. Increasing duration of
immunotherapy was also a significant factor, although no specific
immunosuppressive therapy was noted as a distinct risk factor in this
study.
The increased risk of skin cancer may result from decreased immunosurveillance as well as drug-specific properties [115].
A Swiss study of 48 kidney transplant patients who were receiving
either azathioprine (AZA) or mycophenolate (MMF) evaluated the skin
photosensitivity effects of changing from AZA to MMF [116].
The study results revealed that changing from AZA to MMF did reduce
skin photosensitivity to UVA, but not UVB, in the patient population
tested (primarily skin types II and III). The results from two small UK
studies also indicate increased UVA photosensitivity in patients
taking therapeutic doses of AZA [117, 118].
The use of calcineurin inhibitors has
also been associated with an increased risk for NMSC. One study noted a
2.8 times greater risk of NMSC when cyclosporine was added to an
immunosuppressive protocol of AZA and prednisolone [119].
Another study found that replacing calcineurin inhibitors with
sirolimus reduced the incidence of SCC and lengthened the time to
onset, although adverse events were significantly greater with
sirolimus therapy [115].
Other studies have found no specific
connection between types of immunosuppressive therapy and NMSC risk,
and it is possible that the level of immunosuppression is a more
critical factor than the type [120].
Further comparative research into the association between
immunosuppressive drugs and the incidence of skin cancer will enhance
our understanding of possible risks and may provide valuable strategies
for managing and reducing this risk in the future. For now, it is
important that physicians are aware of these considerations.
A retrospective analysis of the cost
of dermatologic care in one Swiss clinic found that dermatology care
costs for OTR are high, with the majority of costs due to occurrence of
SCC [121]. Once SCC occurs, the costs of care “increase in a pronounced and sustained fashion” [121]. Interventions that limit progression of early lesions to invasive SCC can result in considerable cost savings.
The immunosuppressed population
requires specific targeted surveillance to help ensure early diagnosis
and management of skin cancers. The REAKT Working Group recommends that
OTR and other patients who are immunocompromised receive yearly
comprehensive screening to ensure early diagnosis of SCC in-situ and
timely and aggressive treatment to limit progression. This approach is
likely to improve long-term prognosis as well as reduce the costs
associated with SCC in these populations. Concern has been raised about
the safety of immune stimulators such as imiquimod. However, there is
now a body of evidence suggesting that these substances are safe in OTR
[122].
Funding / potential competing interests:
LEO Pharma has provided financial support for the authors’ meetings
and for medical writing services in preparation of these guidelines.
Gina Kaeuper was the medical writer for these guidelines and was
compensated by LEO Pharma. GH and WHB are consultants to LEO Pharma. OG
is member of scientific advisory boards for LEO and Galderma and has
received speaker honoraria from Leo, Galderma and Alimrall. CM is member
of advisory board dermatology for LEO Pharma.
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