6. Therapy of cheilitis actinica – Actinic keratosis and squamous cell carcinoma of the skin
R.-M. Szeimies, C. Berking, T. Dirschka, A. Hauschild, K. Wermker, U. Leiter, L. Schmitz
6.1 Literature search and study selection
For the evidence-based recommendations and statements, a Medline literature search was conducted on September 3, 2020 that included only comparative randomized or nonrandomized, observational or cross-sectional studies. Study design included RCTs, systematic reviews or meta-analyses of RCTs, with a minimum study population of n≥10.
Casuistics (single and collective), descriptive reviews, papers with a study population less than 10, qualitative reports without quantifiable measurement precision and experimental studies were excluded.
Thirty-five papers were identified after appropriate abstract searches, and 33 full texts were analyzed, including 5 systematic reviews and meta-analyses and 25 individual studies.
6.2 Indication and natural history of the disease
The indication for therapy of cheilitis actinica should be made in synopsis of the clinical presentation, risk factors (e.g. immunosuppression, cumulative UV exposure, involvement of the entire lower lip, involvement also of the upper lip), comorbidities, life expectancy and the patient's wishes.
- Consensus
- Strong consensus (100%)
Before choosing a treatment procedure, a biopsy should be obtained for diagnostic confirmation and to exclude invasive squamous cell carcinoma.
Histological control shall be carried out if there is clinical evidence of a lack of response or incomplete response to therapy.
Actinic cheilitis is divided into an acute and a chronic form. While the former corresponds to dermatitis solaris, the chronic form (cheilosis actinica or cheilitis actinica chronica, CA for short) is a variant of AK in the lip red area. In more than 90% of cases it is localized in the area of the lower lip. Frequently, the entire surface of the red lip is affected, and there is a picture of an extensive, partially atrophic, partially erosive or even scaly skin surface, in the sense of a field cancerization as in other body regions. The erosive-crustose form is also called cheilitis abrasiva praecancerosa (manganotti) and, like all other forms, may progress to invasive SCC if prolonged. Analogous to the progression or regression of AK on other body skin, the course of CA is difficult to predict. However, the occurrence of chronic photodamage in the transitional epithelium with lack of protective functions such as keratinization and melanocyte activity is accompanied by a higher risk of transition into invasive SCC. Although clear figures on this are lacking, a recent review reported this risk to be 10-30% [290][291]. Since 95% of SCC of the lip arise on a CA [291], the indication for treatment of a CA should be made generously, taking into account any other risk factors such as immunosuppression, but also weighing factors such as comorbidities, life expectancy and patient wishes.
6.3 Therapy basics
For the treatment of CA, almost all therapeutic options mentioned for AK are available. However, due to frequent infestation of the entire lip in the sense of a field cancerization, a field-directed therapy is required; i.e., the objective should be treatment of the entire lip region. In this respect, the use of treatment procedures that lead to impairments such as ulceration and crust formation over a longer period of time is often difficult for patients to tolerate because speech and food intake may be restricted along with cosmetic disturbance.
The treatment options evaluated in the literature review predominantly include topical, drug-based procedures, as corresponding studies of higher quality exist for these.
Table 30: Therapy methods for cheilitis actinica
| Ablative procedures | Drug-based procedures |
|
Surgical procedures
|
Topical drug-basedprocedures
|
|
Laser procedures (ablative)
|
Photodynamic therapy
|
| Cryosurgery | |
| Chemical peeling |
Some systematic reviews also compare physical methods (surgery, laser), so these are listed as well, especially since the results may well hold up against topical therapies [291][292]. Post-therapeutic assessment most commonly includes clinical response. In a meta-analysis of 49 studies, dermatoscopy outcome is used in only one study and post-therapeutic biopsies for histopathological assessment are carried out in 34 studies [292].
6.4 Ablative procedures
Ablative procedures include vermilionectomy, i.e., strip surgical removal of affected lip skin followed by mobilization of lip mucosa as a substitute, laser treatment using ablative laser systems (CO2, Er:YAG laser), and electrodesiccation using radiofrequency currents, chemical peeling and cryosurgery [293].
6.4.1 Surgical procedures
Surgical removal of cheilitis actinica (e.g., by vermilionectomy or lip-shave with histological workup and information on the status of resection margins) shall be offered in cases of extensive involvement.
Surgical procedures (mucosal advancement flap, high energy electrodesiccation, lip shave, dermabrasion) were evaluated in 3 systematic reviews [291][292][293]. In the systematic review and meta-analysis by Carvalho et al. [292], a total of 283 cases of CA were treated in such a way in 10 studies. Malignant transformation occurred in 2.5% of surgically treated cases. The weighted remission rate was higher for surgical procedures (92.8%) than for nonsurgical procedures (65.9%). The recurrence rate was lower for surgical procedures (8.4%) than for nonsurgical therapies (19.2%) [292].
In the work by Salgueiro et al. [293] 6 studies with a total of 104 patients were evaluated under the term "surgery“. The procedures studied were vermilionectomy, chemical peeling, cryosurgery and electrodesiccation. Clinical improvement for vermilionectomy was 100% and side effects were described in 10% to 100% of cases, including paresthesia (10-33.3%), infection (10%) and necrosis (10%) [293].
Also, in the prospective, comparative work by Robinson [290], which is also partially included in the systematic reviews, topical 5-fluorouracil 5% solution or chemical peel with 50% trichloroacetic acid showed no recurrences during the median follow-up of 49-51 months for vermilionectomy and CO2 laser treatment, whereas 5-fluorouracil had 5 and chemoexfoliation had 7 clinically suspicious recurrences (10 patients per group each) [290].
In an intraindividual case review between electrodesiccation and CO2 laser in 14 patients, one half of each lower lip with CA was ablated with laser or electrodesiccation. Complete re-epithelialization in the laser area was seen after 14.4 days, whereas the electrodesiccation area healed only after 23.1 days. A clear statement regarding recurrence rates in the respective treatment areas was not made [294]. In a systematic review, vermilionectomy was listed as the most operator-dependent therapeutic procedure because scalpel incisions and suture closure affect optimal lesion clearance and wound healing [296].
In summary, surgical therapeutic procedures are highly effective in the treatment of CA and are particularly useful in cases of extensive spread. Vermilionectomy with scalpel has the additional advantage that the entire excidate is available for histopathologic evaluation and a statement can be made regarding the status of resection.
6.4.2 Laser therapy
6.4.2.1 Ablative laser procedures
Treatment of cheilitis actinica with ablative laser procedures (CO2, Er:YAG) can be offered.
Numerous studies have investigated the use of ablative laser procedures in CA [294][290][297][298][299][300]. Using CO2 or Er:YAG lasers, the diseased tissue was ablated layer by layer. Due to the high energy absorption of the laser light in water, this occurs with both laser systems under vaporization, so that a precise destruction of the CA is possible. Due to a thermally induced coagulation zone, which is somewhat more pronounced with the CO2 laser, intraoperative bleeding can be avoided by sealing the vessel. However, if the tissue is completely vaporized, histopathological examination is not possible. The procedure is highly operator-dependent; if ablation is too shallow, recurrences are common. Aggressive, overly deep ablation can result in wound healing problems and scarring. Herpes recurrence prophylaxis with aciclovir or its derivatives is indicated.
A prospective comparative study [290] compared the use of CO2 laser with 5-FU, peeling, and vermilionectomy. With equal effectiveness of the laser and the surgical procedure, laser ablation resulted in fewer postoperative complications [290]. In a comparison of electrodesiccation with CO2 laser in a hemisphere comparison for histologically confirmed CA in 14 patients in a randomized trial, the CO2 laser performed significantly better in terms of time to re-epithelialization at the same healing rate (see (see) [294]. In a prospective study of 19 patients, CO2 laser vermilionectomy was used to ablate CA from the side with a sharply focused laser beam so that the removed piece of tissue could be submitted for histological evaluation. Complete re-epithelialization occurred after 4-7 weeks. Recurrences were not reported in [297]. In another prospective uncontrolled study of 13 patients, CO2 laser vaporization proved to be a successful treatment modality. No recurrence occurred during the median follow-up period of eleven months. However, three patients showed scarring and one patient experienced hyperesthesia [298]. In a collective case series of 43 patients with CA, after a median follow-up of 29.4 months, recurrence occurred in three cases after CO2 laser vaporization, but invasive SCC also occurred in two cases [299]. An uncontrolled prospective study of twelve patients evaluated the use of an Er:YAG laser in the treatment of CA. The mean healing time to re-epithelialization was 22.33 days, and the mean follow-up time of 23.16 months showed no recurrence [300].
6.4.2.2 Non-ablative laser procedures
Insufficient data currently does not allow recommendations for the therapy of cheilitis actinica with non-ablative laser procedures.
- Consensus
- Strong consensus (100%)
There are no relevant studies or case reports in the literature on the use of non-ablative laser procedures in CA.
6.4.3 Cryosurgery
The data available on cryosurgery do not allow a conclusive recommendation for the therapy of cheilitis actinica.
- Consensus
- Strong consensus (100%)
Only one systematic review mentions an uncontrolled experimental study describing the combined use of imiquimod and cryosurgery for CA [293]. In addition, there are numerous uncontrolled studies from the past century that favor the use of cryosurgery. These include a paper by Lubritz and Smolewski, who treated 53 CA lesions on the lower lip in 37 patients using cryosurgery and observed only one recurrence and one SCC after a follow-up period of at least one year (healing rate of 96.2%) [295]. However, a review of treatment options for CA also found reference to the lack of standardization of cryosurgical treatment, the lack of histological control, and potential side effects such as postoperative edema, pain during and after treatment, scarring, permanent pigmentation changes and local neuropathies [296].
6.4.4 Chemoexfoliation
Chemical peeling shall not be used for cheilitis actinica because of a lack of evidence of benefit.
The systematic review by Salgueiro et al. [293]cites the original work by Robinson from 1989 [290], in which of four comparison groups of ten patients each, one group was treated with trichloroacetic acid 50%. In this one, recurrence occurred in seven cases after a median follow-up time of 49 months. The first recurrence occurred after a median time of nine months [290]. The systematic review by Shah et al. also cited this work, criticized the lack of further controlled studies and therefore did not recommend chemical peeling as a treatment procedure for CA [296].
6.5 Topical drug-based procedures
Drug procedures include classic topical drug applications of pharmaceuticals as well as PDT as a combination of a drug procedure with a procedural approach. These include the pharmaceuticals diclofenac sodium 3% gel, 5-fluorouracil 5% cream, imiquimod 5% cream and 3.75% cream, IMB 0.015% gel (although this not discussed because it is no longer approved in the EMA zone), and for PDT ALA as a 20% preparation or as a patch and MAL 16% as a cream.
6.5.1 Diclofenac
Treatment with diclofenac sodium 3% gel may be offered for cheilitis actinica.
In the three systematic reviews cited [291][292][293], the three prospective studies [301][302][303] on the use of diclofenac sodium 3% gel were listed. In the summary review by Lai et al., a complete clinical response was described in 45.2% of cases (28 of 62), with a complete histopathological response observed in 4 of 6 cases studied. Clinical recurrences occurred in 6.5% of cases (3 of 46) and cosmetic outcome was judged to be excellent in 6 of 6 cases. Treatment discontinuation due to adverse events occurred in 15.2% of cases [291].
In the prospective, uncontrolled study of 31 patients with a clinical diagnosis of CA, diclofenac sodium 3% gel was applied three times daily for 90 days. 19 patients completed the study and were included in the analysis. Ten cases experienced complete remission, three patients experienced partial remission, one patient showed worsening of symptoms and four patients discontinued treatment due to side effects. Follow-up was six months, during which time there were no clinical signs of relapse or disease progression. There was no association between remission, side effects and severity of CA, although an unreviewed score was used to assess severity [301].
In another randomized trial of 30 patients with CA, treatment was given in three groups with either imiquimod 5% cream once daily three days a week for four weeks or a single treatment with 150 µg/g IMB gel for three consecutive days or diclofenac sodium 3% gel twice daily for six weeks [302]. Complete remission occurred in five of the ten patients (50%) for imiquimod, four of ten patients (40%) for IMB, and two of ten patients (20%) for diclofenac sodium. Despite the low response rate, the authors considered diclofenac sodium 3% gel suitable for therapy in certain cases (exfoliative areas and erosions and atrophic areas), also in view of the low inflammatory response and in patients with low pain threshold [302].
In the prospective uncontrolled study of 34 patients with CA, Lima et al. investigated the effect of diclofenac sodium 3% gel over the period of 30-180 days twice daily [303]. Of the 27 patients who completed the study, 12 (44%) showed complete remission clinically and 15 (56%) had partial remission. Due to the good tolerability, few side effects and good aesthetic results, the authors considered the treatment promising [303].
6.5.2 5-fluorouracil
Two systematic reviews described the use of 5-fluorouracil 5% for the treatment of CA [291][293]. Both papers also mentioned Robinson's prospective comparative study in which a five percent 5-fluorouracil solution was applied to the lower lip of affected patients three times daily for 14 days in one treatment arm [290]. After a median follow-up of 50 months, clinical recurrence was seen in five cases (50%), with a median of twelve months. In the review by Lai et al., 5-fluorouracil 5% resulted in clinical healing in 68.2% (total of 22 patients), but no histological healing (6 cases studied). In 10% of cases, therapy was discontinued due to side effects [291].
6.5.3 Imiquimod
A systematic review described the use of imiquimod 5% for the treatment of CA [291]. Thirty patients received imiquimod 5% for varying periods of time. A complete clinical response was reported in 73.3% of cases (22 of 30), but complete histological healing occurred in only 2 of the 5 cases studied [291]. In the only retrospective study of 15 patients with histologically confirmed CA that could be evaluated for this purpose, topical treatment with imiquimod 5% was given 3 times weekly for 4 to 6 weeks [304]. Patients with a history of labial herpes were treated prophylactically with valaciclovir 1g/daily during imiquimod application. In all 15 patients, CA healed 4 weeks after completion of imiquimod treatment. Nine of the patients were followed up for at least another 3 months and showed no recurrence. 60% of patients experienced moderate to more severe local side effects such as erythema, induration, erosions, or ulceration, some of which persisted throughout the duration of therapy [304]. For 3.75% imiquimod, only one collective case report exists with 11 patients, including only one patient with CA who reported improvement [305]. With the currently (as of 08/2021) available preparations, contact with the lips should be avoided.
6.5.4 Photodynamic therapy
Photodynamic therapy with red light illumination and 5-aminolevulinic acid (ALA) or its methyl ester (MAL) should be offered for therapy of cheilitis actinica.
Methyl aminolevulinate (MAL) in combination with natural or simulated daylight (MAL-dlPDT) should be offered for therapy of cheilitis actinica.
There are numerous well-documented studies and systematic reviews on the use of PDT in CA. A systematic review from 2015 compared the two sensitizers ALA and MAL [313]. The median histological cure rate, if examined, was 47.4% (observation time between 1.5-18 months) for the studies with more than 10 patients. The median complete remission rate was reported to be 58% for 5-ALA and 62.5% for MAL [313]. After a single 5-ALA application (20% cream) followed by illumination with incoherent red light (40 J/cm²), Sotiriou et al. achieved a complete remission of 80% in 10 patients in a prospective, uncontrolled study, considering histological confirmation of the clinical outcome [306]. In another prospective, uncontrolled study of 40 patients with histologically confirmed CA by the same group, 26 patients showed a complete clinical response after 5-ALA-PDT twice. After six months, three patients had clinical and histological recurrence, and after another six months, one patient had recurrence. After 18 months, the overall clinical recurrence rate was 15.38%, and the histological recurrence rate was 34.61% [307]. Histological outcome was considered excellent in more than 80% of cases.
In a prospective, uncontrolled study of 15 patients with histologically confirmed CA, Berking and coworkers achieved complete clinical healing in 47% (7/15) and partial healing also in 47% (7/15) of patients after two sessions of MAL-PDT at the time of follow-up at three months [308]. However, histopathological workup found residual disease in 62% (8/13). Five patients (38%) showed histological healing, and no recurrence occurred in further follow-up to 22 months of three completely healed patients [308]. In another prospective, uncontrolled study of 23 patients, MAL-PDT was also carried out twice, two weeks apart [309]. Three months after treatment, 16 patients could be evaluated. These showed a complete clinical response in 62.5%, and 37.5% still had clinical signs of CA. However, all patients still showed histopathological changes consistent with CA [309]. In another prospective, uncontrolled study of 19 patients, MAL-PDT was performed only once. After 60 days, patient satisfaction was determined and a biopsy was performed [310]. In 84% of the cases, dysplastic changes could still be detected histologically. A correlation between the final satisfaction of the patients, the subjective impression of clinical improvement and the degree of determined dysplasia was not shown [310].
In a retrospective analysis of eleven cases with CA, conventional PDT with a 5-ALA-containing patch was studied [311]. After four hours of incubation, patients received illumination with narrow-spectrum red light (37 J/cm²). A complete clinical response at three months was observed in eight of eleven patients (72.7%), with recurrences in two lesions at twelve months. Thus, complete clinical healing one year after patch PDT was 66.6% (10/15 lesions). The cosmetic outcome was judged to be excellent in all cases [311]. In another prospective, uncontrolled study by the same research group in 21 patients with the same treatment protocol, 19 patients completed the study [312]. Three months after PDT, 17 patients (89.5%) had complete remission. Complete clinical cure one year after single 5-ALA patch PDT was 84.2% [312].
There are also two well-documented, prospective clinical trials for daylight PDT [314][315]. In the study by Levi et al., 11 patients were treated repeatedly (every 2-4 weeks) with daylight PDT after prior application of MAL. The mean number of treatments was 2.7, and the mean follow-up time was 30 months (6-60 months). The healing rate achieved was 91% (10/11). Patients reported only mild erythema and little to no pain during treatment [314]. Another prospective study using MAL daylight PDT included 22 patients with histologically confirmed CA [315]. 20 patients completed the study. After three months, 18 of 20 patients (90%) achieved complete remission. Twelve months after daylight PDT, complete clinical remission was 80% (16/20). Mild CA, histologically designated as grade I, seemed to heal better (100%) than more pronounced lesions (grade II, 50%) [315].
6.6 Combination therapies
Combination procedures found via the search strategy included a study in which CA was first pretreated with ablative fractional Er:YAG laser followed by PDT with MAL [316]. In a randomized trial of 33 patients with histologically confirmed CA, one half received pretreatment with Er:YAG laser followed immediately by a single session of red light PDT with MAL (3-h incubation, illumination with LED system, 37 J/cm²). The other half received two cycles of MAL-PDT without prior laser treatment, 7 days apart. Evaluation of clinical and histopathological outcome took place 3 and 12 months after therapy. At 3 months, the population pretreated with laser showed significantly more effective healing (92% complete response) than the group treated twice with MAL-PDT alone (59%, p=0.040). At 12 months, the healing rate for laser-assisted PDT remained at 85%, while it decreased to 29% for conventional PDT [316]. The authors stated a significant advantage of pretreatment using ablative fractional Er:YAG laser over conventional MAL-PDT for CA.
In another prospective, uncontrolled study, Sotiriou et al. combined two conventional MAL-PDT sessions in 43 patients with histologically confirmed CA with subsequent application of 5% imiquimod cream 3 times weekly for 4 weeks [317]. After 3 months, 30 patients were evaluated and a complete clinical response was observed in 27 patients. At 12 months, the clinical healing rate was 80% and histological healing was 73%. Treatment was well tolerated and side effects were as expected and temporary [317].
In summary, the presented combination forms show good potential for increasing effectiveness; however, the data are currently still too minimal to make a therapy recommendation.
6.7 Summary and balancing presentation of approved therapy options (balance sheet)
Table 31: Balance sheet interventions for cheilitis actinica
|
Intervention |
TA |
Mechanism of action & Application |
Effectiveness1 |
Side |
Cosmetic outcome (investigator and patient assessment)3 |
Duration of |
Direct treatment costs per cycle5 |
Pract.6 Physician |
Practitioner6 Patient |
|
|
Ablative procedures |
||||||||||
|
Cryosurgery |
L |
One to two freeze-thaw cycles with liquid nitrogen (-196°C) |
++/+++ (No data available from RCT)8 |
++ |
+ |
6 |
€ |
++++ |
+++ |
~ EC |
|
Surgical procedures with histological control6 |
F |
Complete excision, vermilionectomy or lip-shave. |
++++ (No data available from RCT)8 |
++ (No data available from RCT)8 |
++ (No data available from RCT)8 |
6 |
€-€€ |
+++ |
++ |
éé 1-3 |
|
Surgical procedures without histological control6 |
F |
Electrodesiccation, dermabrasion |
+ (No data available from RCT)8 |
+ (No data available from RCT)8 |
+/++ (No data available from RCT)8 |
6 |
€-€€ |
+/++ |
+ |
~ EK |
|
Chemical peelings |
F |
Ablation of upper skin layers using chemical agents (e.g. 50% trichloroacetic acid) |
+ Healing rate: 30% |
+/++ |
++ |
6 |
€-€€ |
++ |
++ |
~ 1-4 |
|
Laser procedures6 |
F |
Ablative laser procedures (e.g. CO2 laser-, erbium YAG laser) |
+++ Healing rate: 93.4% |
++ |
++/+++ |
6 |
€€€ |
+++ |
++ |
⇔ 2-3 |
|
Non-ablative laser procedures6 (e.g. e.g. Nd:YAG laser, fractional 1540 nm laser) |
+ (No data available from RCT)8 |
++ (No data available from RCT)8 |
++ (No data available from RCT)8 |
6 |
€€€ |
+++ |
+++ |
~ EC |
||
|
Topical drug-based procedures |
||||||||||
|
Diclofenac sodium 3% gel (Solaraze®) |
F |
Cyclooxygenase-2 inhibitor |
++ Healing rate: 45.2% |
+++/ ++++ |
+/+++ |
666 |
€-€€ |
++++ |
++ |
⇔ 2-3 |
|
5-Fluorouracil 5% Crème |
F |
Cytostatic drug |
+++/++++ Healing rate: 50-68.2% |
++ |
++/++++ |
66 |
€-€€ |
+++ |
+++ |
~ EC |
|
Imiquimod 3.75% Crème |
F |
Toll-like receptor 7 agonist 1x daily for 2 weeks, 2 weeks off, 1x daily for 2 weeks (interval therapy) Up to 2 sachets of 250 mg imiquimod cream per sachet per use. |
+ |
++ |
+++ |
66 |
€€ |
+++ |
+++ |
~ EC |
|
Imiquimod 5% Crème |
F |
Toll-like receptor 7 agonist |
++ Healing s-rate 40-73,3% |
++ |
+++ |
66 |
€€ |
+++ |
+++ |
~ EK |
|
ALA-PDT (Alacare®) |
F, L |
Protoporphyrin precursor (photosensitizer) |
+++/++++ Healing rate: 66,6-84,2% |
++ |
+++/++++ |
6 |
€€-€€€ |
++/ +++ |
++ |
é 2-3 |
|
ALA-PDT |
F |
Precursor of protoporphyrin (photosensitizer)
|
+++/++++ Healing rate: 58.0%-80%. |
++ |
+++/++++ |
6 |
€€-€€€ |
++/ +++ |
++ |
é 2-3 |
|
MAL-PDT |
F |
Precursor of protoporphyrin (photosensitizer). Application of MAL, light protection and occlusive dressing for 3 h, illumination with red light for approx. 10-20 min, repeat after 4-12 weeks if necessary. |
+++/++++ Healing rate: 47%-62.5% |
++ |
+++/++++ |
6 |
€€-€€€ |
++/ +++ |
++ |
é 2-3 |
|
DL-MAL-PDT |
F |
Protoporphyrin precursor (photosensitizer) |
+++ Healing rate: 80%-91% |
++++ |
+++ |
6 |
€€ |
++ |
++++ |
é 3 |
|
1 Semiquantitative representation considering lesion- and patient-related response rates (+ = |
||||||||||
Evidence tables
Cheilitis actinica: SR und Meta-Analysen
|
Study |
Aims |
Design |
Population |
Outcomes |
Results |
Comments |
LoE |
|
Brignardello-Petersen R et al 2019 |
To assess the effects of the treatments for AC |
Systematic review |
Patients with actinic cheilitis |
Efficacy |
29 studies that evaluated several types of treatments were found. Laser therapy was evaluated in 19 studies in which researchers enrolled 503 patients. The studies assessing low-power lasers showed that 43% through 100% of the patients improved clinically but that there was a high frequency of adverse events. The studies assessing high-power lasers showed that 60% through 100% of patients improved clinically, but the adverse events were more severe. The 7 studies assessing chemotherapeutic agents included a total of 105 patients. The proportion of patients who improved clinically ranged from 80% through 100%. Adverse effects ranged from 10% through 100%. Researchers assessed surgery in 6 studies in which 104 patients were included. Clinical improvement was seen in 100% of the patients, and adverse effects ranged from 10% through 100%. Anti-inflammatory drugs were assessed in 2 studies in which researchers included 33 patients. Clinical improvement was seen in 44% through 67%. Rates of histologic improvement were lower for all treatment options. |
The authors did not provide a description of the degree of severity of the AC, which would have facilitated proper use of this evidence. In addition, they did not describe separately the results from the controlled studies to provide a less biased comparison between options. In summary, the results of this SR show that the rate of clinical improvement in patients with AC is high for most treatment options when patients are seen as good candidates for each treatment |
1 |
|
Carvalho MV et al 2018 |
The aim of this systematic review was to compare outcomes between surgical and non-surgical treatment of actinic cheilitis (AC). |
A systematic review and meta-analysis based on the Preferred Reporting Items for Systematic reviews and Meta-Analyses guideline |
Search of PubMed/MEDLINE, Web of Science, and Cochrane Library databases Articles were selected based on the inclusion criteria: randomized clinical trials, prospective/retrospective studies, and case series with at least 10 patients, with a minimum follow-up period of 6 months. A weighted remission rate (RER) and recurrence rate (RR) with a 95% confidence interval was performed. Data analysis was performed using a comprehensive meta-analysis software |
Remission rate and recurrence rate |
A total of 283 ACs in 10 studies were included. About 2.5% surgically treated cases underwent malignant transformation. The weighted remission rate was higher for surgical (92.8%) compared to non-surgical treatment (65.9%). The recurrence rate was lower for surgical (8.4%) compared to non-surgical treatment (19.2%).
|
In this systematic review, the surgical treatment was more favorable than non-surgical for AC. Meanwhile, further studies are needed that should maxi- mize methodological standardization and have greater rigor of the data collection process.
|
1 |
|
Lai M et al 2019 |
Systematic review in order to define the best therapies of actinic cheilitis in terms of clinical response and recurrences. |
Systematic review |
Patients diagnosed with actinic cheilitis |
|
444 papers and 49 were finally considered, including 789 patients and 843 treated areas. The following therapies were recorded in order of frequency: laser-therapy, photodynamic therapy (PDT), 3% diclofenac in 2.5% hyaluronic acid, PDT+5% imiquimod, ALA- or MAL- laser, 5% imiquimod, fluorouracil, partial surgery, 0.015% ingenol mebutate, 50% trichloroacetic acid and laser+PDT. Concerning the primary outcome 85.9% of patients underwent 13 complete clinical response and 11.0% had clinical recurrences. Partial surgery and laser therapy showed the highest complete response rates (14/14 [100%] and 244/260 [93.8%], respectively) with low recurrences. Only a limited number of patients were treated with other therapies, with the exception of PDT with 68.9% complete responses and 12.6% of recurrences. Interestingly, when combined with 5% imiquimod efficacy of PDT was significantly enhanced. Limitations: Heterogeneity across studies. |
Laser therapy appears as the best option among non-surgical approaches for actinic cheilitis, while PDT showed higher efficacy when sequentially combined with 5% imiquimod. Larger studies are needed to confirm these data. |
1 |
|
Salgueiro AP et al 2019 |
To identify the best therapies for actinic cheilitis using a computer-based systematic search conducted on electronic databases |
Computer-based systematic search |
29 journal articles |
Efficacy |
Results were divided according to the type of treatment employed: laser therapy, chemotherapy agents, surgical treatment, and application of anti-inflammatory agents. Clinically, photodynamic therapy showed positive results, with improvement in up to 100% of the patients; however, histopathological improvement varied greatly, from 16 to 100%. Among the chemotherapeutic agents assessed, imiquimod showed the best results: clinical improvement in 80 to 100% of the patients, and histopathological improvement in 73 to 100%. Regarding studies describing surgical approaches, the main focus was the search for the best technique, rather than the cure of AC. Finally, studies employing anti-inflammatory agents are sparse and have small samples, thus providing limited results. |
The scientific evidence available on the treatment of AC is scarce and heterogeneous, photodynamic therapy, and imiquimod application are promising. |
1 |
|
Yazdani Abyaneh MA et al 2015 |
To systematically review the safety and efficacy of PDT for AC |
Systematic review
|
The terms “photodynamic,” “actinic,” “solar,” “cheilitis,” and “cheilosis” were used in combinations to search the PubMed database |
Safety and efficacy |
The authors identified 15 eligible case series encompassing a total of 242 treated subjects. Among studies that evaluated subjects for complete clinical response, 139 of 223 subjects (62%) showed complete response at final follow-ups ranging from 3 to 30 months. Among studies that evaluated subjects for histological outcome, 57 of 121 subjects (47%) demonstrated histological cure at final follow-ups ranging from 1.5 to 18 months. Cosmetic outcomes were good to excellent in the majority of subjects, and adverse events were well tolerated.
|
Photodynamic therapy is safe and has the potential to clinically and histologically treat AC, with a need for future randomized controlled trials. |
1 |
Cheilitis actinica: Einzelstudien
|
Study |
Aims |
Design |
Population |
Outcomes |
Results |
Comments |
LoE |
|
Alamillos-Granados, et al 1993 |
To propose a quick, outpatient procedure that yields good cos- metic, clinical and, functional results and allows histologic examination of the ablated vermilion |
Prospective study; n=19 |
Patients diagnosed with actinic cheilitis and referred for therapy in one center |
Cosmetic, clinical and, functional results after vermilionectomy using CO2 laser |
Seven patients experienced pain the first 2 or 3 days after the operation. Two of them required an analgesic. Five patients had slight swelling that disappeared by the fifth postoperative day. In two patients, bleeding developed the second postoperative day and required electrocoagulation or ligation of a small vessel Complete epi- thelization was achieved in 4 weeks in 14 patients, 5 weeks in 2, 6 weeks in two, and 7 weeks in one patient. The cosmetic result was good in all cases and the procedure had excellent patient acceptance. After epithelization, three patients developed a fibrous band in the lower lip that softened after 6 months and did not interfere with normal lip function. |
CO2 laser vermilionectomy has the advantages of both scalpel vermilionectomy and CO2laser vaporization of the vermilion. It is a quick, definitive, esthetic form of treatment. As with vaporization, there is little postoperative pain or edema. The technique is done under local anesthesia in an outpatient setting, and is well tolerated by the patients. Epithelization occurs within 4 to 7 weeks (4 weeks for most patients) and no special care is necessary. The excised vermilion may be sent for histologic examination, thus allowing for further treatment if malignancy is present. |
3 |
|
Andreadis D et al 2020 |
To assess long-term efficacy of photodynamic therapy with the use of the day light (DLPDT) in actinic cheilitis as well as safety and tolerance. |
Prospective study; n=22 |
Patients histologically diagnosed with AC (grade I dysplasia—affecting no more than one-third of the total epithelium, and grade II dysplasia—affecting no more than two-thirds of the total epithelium) |
Long-term efficacy, safety and tolerance |
Ages ranged from 48–83 years (mean ± SD, 67.5 ± 9.43). Clinical changes at baseline consisted of crusting, scaling, fissuring, and superficial erosions.
Dermoscopic changes mainly included alternations of white and pink structureless areas, scales, erosions, and whitish peripheral projections. Seventeen patients had not received any previous treatment, while three patients had been treated previously with cryotherapy. The study was completed by 20 patients (17 males and 3 females). Two patients were lost to follow-up and were thus not included in the analysis. Baseline histological examination revealed grade I AC in 12 patients and grade II AC in 8 patients. Mean outdoor temperature during DLPDT sessions was 20.83 ± 4.68°C (range 15–28 °C). At 3 months, 18 of the 20 (18/20, 90%) patients achieved complete CR. Two patients achieved only partial response, were biopsied, and histopathological examination confirmed alterations indicative of AC. At the 6-month follow-up visit, one patient showed the signs of clinical recurrence that was histologically confirmed. At the last follow-up visit, 12 months after treatment, clinical recurrence confirmed by histology was recorded in one more patient. Sixteen out of the twenty (16/20) patients included in the analysis remained both clinically and dermoscopically disease free. Thus, according to our results, the overall complete clinical cure rate achieved 12 months after treatment was 80%. Of note is that partial response at the 3-month follow-up and recurrences at the 6- and 12-month follow-up visits were observed only in patients with the initial grade II dysplasia. According to this observation complete clinical cure rate in grade I AC was achieved in 100% (12/12) of the patients, while complete cure rate of grade II AC decreased from 75% (6/8) 3 months after treatment to 50% (4/8) 12 months after treatment. An association between treatment response 12 months post-treatment and grade of dysplasia was observed [χ2(2) = 7.500, p = 0.024, Monte Carlo method’s result p = 0.016, 99% CI 0.013–0.019, Cramer’s V = 0.612], while no statistically significant association between treatment response 3 months (Fisher’s exact test, p = 0.147) and 6 months [χ2(2) = 5.294, p = 0.071, Monte Carlo method’s result p = 0.050, 99% CI 0.045–0.056] post-treatment and grade of dysplasia was observed. There were no unexpected safety issues during treatment and follow-up period. |
DLPDT seems to be of significant benefit for grade I AC. As the treatment procedure is well tolerated and associated with only mild and transient side effects, it could be used as a first-line treatment for AC with grade I dysplasia. Combination with other treatment modalities and more treatment sessions may be necessary to improve efficacy in grade II AC. |
3 |
|
Berking C et al 2007 |
The objective was to assess the efficacy of photodynamic therapy (PDT) in the treatment of actinic cheilitis of the lower lip |
Prospective, uncontrolled study; n=15 |
Patients with actinic cheilitis |
Efficacy |
Complete clinical cure was observed in 47% (7/15) and partial cure in another 47% (7/15) of the patients. By histopathologic analysis, residual disease was found in 62% (8/13). Cosmetic results and patients’ satisfaction were good to excellent in most cases. Local pain was sufficiently controlled by local anesthesia. |
PDT can be an effective noninvasive method to treat actinic cheilitis of the lower lip |
3 |
|
Castiñeiras I et al 2010 |
To evaluate the results obtained after treatment of AC by CO2 laser vaporization in comparison with other treatment modalities and the evolution rate of AC to SCC after CO2 laser treatment. |
Retrospective review; n= 43 |
Patients with AC treated with CO2 laser vaporization at one center from 2002 to 2006 |
Results obtained in patients who had been treated by CO2 laser vaporization for AC, comparison with other treatment modalities and, in particular, to evaluate the evolution rate of AC to SCC after CO2 treatment. |
After a mean follow-up period of 29.4 months, 3/43 treated AC showed local recurrence. Another two patients developed SCC in the treated field. A residual scar was clinically evident in two patients. |
CO2 laser vaporization with an adequate postoperative follow-up is an effective treatment for chronic AC. Nevertheless, some patients (4,6%) went on to develop lip SCC. The follow-up of these patients is mandatory. |
4 |
|
Chaves YN et al 2017 |
To conduct clinical and laboratory evaluation by histopathology and immunohistochemistry of the efficacy of actinic cheilitis treatment using photodynamic therapy (PDT) with methyl aminolevulinate (MAL) and noncoherent red light. |
Prospective uncontrolled study; n=23 |
Patients with actinic cheilitis detected by histopathological examination submitted to two sessions of photodynamic therapy with a two-week interval between them |
Efficacy |
Of the 23 patients who underwent biopsy, 16 completed two photodynamic therapy sessions and the material of one patient was insufficient for immunohistochemistry. Complete clinical response was achieved in 62.5% (10 of 16 patients) and 37.5% still remained with clinical evidence of AC. In spite of this, no case of cure by histopathological analysis was found. There was no significant statistical change among the values of Ki-67, survivin, and p53 observed before and after treatment. |
Photodynamic therapy, as carried out in this trial, was not an efficacious therapeutic option for treating patients with actinic cheilitis included in this sample. |
3 |
|
Choi SH et al 2015 |
The aim of our study was to compare efficacy, recurrence rate, cosmetic outcome and safety between erbium:yttrium–aluminium–garnet ablative fractional laser-assisted methyl aminolaevulinate–PDT (Er:YAG AFL MAL-PDT) and standard MAL-PDT. |
Randomized study; n=33 |
Patients with histologically confirmed AC |
Efficacy, recurrence rate, cosmetic outcome and safety |
In the per-protocol (PP) population, Er:YAG AFL MAL-PDT was significantly more effective (92% complete response rate) than MAL-PDT (59%; P = 0040) at the 3-month follow-up, and differences in efficacy remained significant at the 12-month follow-up (85% in Er:YAG AFL MAL-PDT and 29% in MAL-PDT). The recurrence rate was significantly lower for Er:YAG AFL MAL-PDT (8%) than for MAL-PDT (50%) group at 12 months (P = 0029). No significant difference in cosmetic outcome or safety was observed between Er:YAG AFL MAL-PDT and MAL-PDT. |
Ablative fractional laser pretreatment has significant benefit for the treatment of AC with PDT. |
2 |
|
de Oliveira Bezerra HI et al 2019 |
The objective of the study is to assess, by clinical follow-up, the efficacy of the dermatological cream fludroxycortide 0.125 mg/g (Drenison®) in the treatment of actinic cheilitis (AC) |
Prospective uncontrolled study; n=33 |
Patients diagnosed with AC |
Efficacy |
In the group treated with Fludroxycortide (n = 15), five patients showed total improvement, seven presented partial improvement, and three showed no clinical change. Concerning the patients treated with LS (n = 8), one presented total remission of the clinical lesion characteristics, four exhibited partial improvement, and three exhibited no clinical lip alteration. No case presented symptom worsening. Of the 15 patients undergoing corticotherapy, 12 were satisfied and reported that the product was not irritating and contributed to lesion improvement. |
Conventional treatment with LS was effective in the remission of some AC lesions, but treatment responses were improved when associated with Fludroxycortide, especially in the more severe cases. |
3 |
|
Dufresne RG et al 1998 |
To evaluate the results with CO2 laser treatment in both conventional and super pulsed modes for vermilion ablation |
Prospective, uncontrolled study; n=13 |
Patients with chronic actinic cheilitis of the lower lip |
Efficacy |
The procedure was well tolerated. All patients were able to take fluids immediately, and several patients had no interruption in their routine dietary habits. None had pain that required narcotics. Two patients with minor pain at 4 and 7 days were treated successfully with viscous lidocaine. Re-epithelialization usually occurred by 3 weeks and was completed in all patients by 4 weeks. Focal scarring, none of which was functionally restrictive, developed in three patients. No scar was detected in the three patients who h a d prior lip excisions; their previous surgical scars were undetectable. Only one patient reported dysesthesia. There were no recurrences in any of the patients, with an average follow-up of over 11 months. |
CO2 laser vaporization offers a well-tolerated treatment modality for chronic actinic cheilitis. |
3 |
|
Gonzaga AKG et al 2018 |
The aim of this research was to analyze the efficacy of diclofenac sodium 3% gel in the treatment of this condition, through clinical follow-up |
Prospective uncontrolled study; n=31 |
Patients diagnosed with AC |
Efficacy |
Twelve cases abandoned the treatment for reasons unrelated to the study. Ten participants showed total remission of all clinical features of the lesion and three had partial improvement of the characteristics. One participant presented worsening of clinical condition, and in five cases, treatment was discontinued due to development of mild adverse effects at the site of gel application. Regarding satisfaction analyses and tolerability to the drug, from 14 patients who completed treatment without adverse effects or complications, most agreed fully that they were satisfied with the therapy (n=11) and that the drug was not irritating to the mouth (n=9). Patients are being monitored without clinical signs of recurrence and/or progression of the lesions. |
Topical application of the drug has provided a convenient and well-tolerated in most cases. Diclofenac sodium gel (3%) may be a promising alternative for treatment of actinic cheilitis |
3 |
|
Husein-ElAhmed H et al 2018 |
To compare the clinical efficacy of imiquimod (IMI), ingenol mebutate (IMB) and diclofenac (DIC) in AC |
Randomized study; n=30 |
Patients diagnosed with AC and treated in one center |
Efficacy |
Ten patients were assigned to each drug. Complete clearance of AC was achieved in 5 (50%) of the 10 patients treated with IMI, 4 (40%) of the 10 patients treated with IMB and 2 (20%) of the 10 patients treated with DIC (Figs 1, 2). The clearance with IMI was statistically similar to that of IMB (P = 0.22), but significantly greater than with DIC (P = 0.03). Persistence of both leucoplasia and keratotic plaques was significantly more common in patients treated with DIC compared with either IMI (P < 0.05) or IMB (P = 0.05). Unstructured vermillion border persisted in 1 patient (10%) treated with IMI, 2 patients (20%) treated with IMB and 4 patients (40%) treated with DIC, but these differences were not statistically significant (P > 0.05). Similar outcomes were observed for dyschromic and/or atrophic areas. Exfoliative areas cleared up completely in all patients regardless of the therapy used. Table 2 provides further details on the results
In this study, we found that IMI was the most clinically effective therapy compared with IM or DIC. However, IM was not inferior to IMI, and as it has the shortest posology, it is the best choice for patients who have difficulties in adherence to therapy, e.g. patients with neurological disorders such as dementia. In patients with leucoplakia, keratotic plaques or involvement of the vermilion border, both IMI and IMB were acceptable, but DIC should be avoided as it had the lowest rate of response for all three of these conditions. DIC is more suitable for AC with exfoliative areas and erosions, and in absence of deeper signs of AC such as atrophic areas. Furthermore, owing to its low inflammatory reaction, DIC is an acceptable option for subjects with low pain threshold. |
both IMI and IM produced a better response than DIC, but the latter has characteristics that may make it more useful for certain types of AC. Therefore, this novel study suggests that each drug may have specific clinical types of AC for which it is better suited.
|
2 |
|
Laws RA et al 2000 |
To compare two treatment modalities (CO2 laser resurfacing and electrodessication) for the treatment of biopsy-confirmed actinic cheilitis. |
Randomized bi- lateral study; n=14 |
Patients with biopsy-proven actinic cheilitis |
Histologic cure, cosmetic outcome, and complication rate |
The CO2 laser-treated side was reepithelialized after an average of 14.4 days (range 7–23 days). The side treated with electrodessication was reepithelialized after an average of 23.1 days (range 11–37 days), which was significantly longer than the side treated with CO2 laser (paired t-test, P <.001 in the patients treated with scroll-shaped electrode comparison of co2 laser electrodessication still demonstrated a significant difference healing time days versus p=".004).</span"> All patients described minimal to no pain at the first follow-up visit, 18 hours after the procedure. The most common scenario, described by 12 of the 14 patients, was a moderate burning discomfort beginning 3–6 hours after the procedure, and lasting 12 hours. Twelve patients required only plain acetaminophen for pain. Patient 14 received several hours of sun exposure during the first 10 days of healing, and complained of a new onset of burning which lasted for 1–2 days. Of interest, he also had the longest healing time of all the patients. With respect to all patients, there was no difference in perceived pain between the two treatment sides (repeated measures analysis of variance, P = .817). At the 3-month follow-up visit, the appearance of the lip was improved in all patients, and both sides of the lip appeared identical in all 14 patients. Five of the 14 patients agreed to undergo a 3-month follow-up biopsy. |
Electrodessication is an attractive, practical alternative to CO2 laser ablation when used to treat actinic cheilitis. |
2 |
|
Levi A et al 2019 |
To determine the safety and efficacy of daylight photodynamic therapy (PDT) in a series of patients with actinic cheilitis |
Prospective uncontrolled study; n=11 |
Patients with actinic cheilitis |
Safety and efficacy |
Cure rate was 91% (10 of 11 patients, three females/eight males; mean age 59.2 ± 14.4 years). Mean number of treatments to attain cure was 2.7. Patients experienced mild erythema and minimal to no pain during treatment. |
Daylight PDT is a promising modality for the treatment of AC, with impressive cosmetic results and few side effects. Actinic cheilitis is a common premalignant condition of the lower lip that requires treatment to prevent its progression to squamous cell carcinoma. We describe our therapeutic experience using daylight photodynamic therapy. Treatment sessions continued until achieving clinical and histological remission. Symptoms were resolved in 10 of 11 patients (91%) after a median of two (range 1-6) treatments, with only few adverse effects. Daylight photodynamic therapy is a promising modality for the treatment of actinic cheilitis.
|
3 |
|
Lima Gda S et al 2010 |
To evaluate the effect of 3% diclofenac in 2.5% hyaluronic acid gel in the treatment of actinic cheilitis |
Prospective uncontrolled study; n=34 |
Patients with actinic cheilitis |
Efficacy |
Of the 27 patients that completed the study, 12 (44%) showed complete remission of the whitish plaques and exfoliative areas, and 15 (56%) had partial remission of the clinical picture of cheilitis. The latter group was submitted to excision of the leukoplakic areas which diagnosis varied from mild to moderate epithelial dysplasia. |
The results suggest a promising role for diclofenac in hyaluronic acid gel in the treatment of AC. This treatment has the advantages of not being invasive and showing few side effects. |
3 |
|
Orenstein A et al 2007 |
To evaluate the efficacy and outcome of a new modality in the treatment of actinic cheilitis with the Er:YAG laser |
Prospective uncontrolled study; n=12 |
Patients with actinic cheilitis were treated at one center institute with the Er:YAG laser between 2002 and 2005 |
Efficacy |
Patients were men and women aged between 37 and 71 years. The healing duration varied from 7 to 30 days (mean 22.33-6.91 days) and the follow-up ranged from 8 months to 3 years (mean 23.16-9.48 months). No recurrences were detected in our study. |
Using the Er:YAG laser provides accurate tissue ablation, giving a very satisfactory cosmetic result, with a short healing period, no lip deformity and no sensation loss. |
3 |
|
Paolino G et al 2020 |
To assess the efficacy and tolerability of imiquimod 3.75% in treating actinic keratosis, pigmented basal cell carcinomas, and actinic cheilitis |
Case series report; n=11 |
Patients with actinic keratosis, pigmented basal cell carcinomas, and actinic cheilitis |
Efficacy and tolerability |
All patients experienced local skin reactions (LRS), with erythema that was the most common LRS followed by, edema, scaling, crusting, and erosions. Each LSR did resolve, without causing aesthetic alterations. Compared to topical imiquimod 5%, topical imiquimod 3.75% cream has an acceptable tolerability profile, with a short and simple treatment regimen. Besides, despite the lower percentage compared to topical imiquimod 5% cream, imiquimod 3.75% cream shows also effectiveness in the case of pigmented BCCs and actinic cheilitis, as reported in our patients. |
In conclusion, imiquimod 3.75% cream is characterized by an acceptable tolerability profile and has the advantage of being self-applied by the patients,4 showing an efficacy not only at the level of AKs but also in nodulocystic pigmented BCCs and actinic cheilitis. |
4 |
|
Radakovic S et al 2020 |
To evaluate the efficacy, tolerability, safety and cosmetic outcome of Alacare patch PDT for AC |
Prospective uncontrolled study; n=21 |
Patients with actinic cheilitis |
Efficacy, tolerability, safety and cosmetic outcome |
Nineteen patients completed the study. Three months after PDT, 17 patients (89.5%) had achieved complete remission. Of these, one patient presented with recurrence of AC at the 6-month follow-up, whereas all other patients remained in remission until the end of the observation period. The complete clinical cure rate at 1 year after a single Ala- care patch PDT thus was 84.2%. Pain during illumination and the phototoxic skin reaction were in general mild to moderate. The cosmetic outcome was excellent. |
The present prospective study on Alacare patch PDT for AC confirms its high clinical efficacy, good tolerability and favourable cosmetic effects. Alacare patch PDT should be considered as a valid treatment option for patients with AC. |
3 |
|
Radakovic S et al 2017 |
To assess the efficacy, tolerability and cosmetic outcome of Alacare patch-PDT in eleven patients with AC |
Retrospective analysis; n=11 |
Patients with actinic cheilitis |
Efficacy and safety |
Complete clinical response at the 3-month follow-up was achieved in eight of 11 patients (72,7%) and 12 of 15 AC lesions (80,0%), respectively. Up to the final 12-month follow-up, a recurrence was observed in two lesions. The complete clinical cure rate at 1 year after Alacare patch-PDT, thus, was 66,6% (10/15 lesions). The cosmetic outcome of the treatment was excellent in all cases. |
Alacare patch-PDT was found to have substantial efficacy in the treatment of mild to moderate AC. Given its ease of use, absence of long-term side effects and the excellent cosmetic results Alacare patch-PDT might be considered as a promising new treatment option for the management of AC. |
4 |
|
Ribeiro CF et al 2012 |
To assess the efficacy of single photodynamic therapy (PDT) session using 16% methyl-aminolevulinate and its cosmetic results. |
Prospective uncontrolled study; n=19 |
Patients with actinic cheilitis of the lower lip |
Efficacy |
The sample was composed of 19 patients (10 males and 9 females), phototypes I to III, with average age of 62 years. Main adverse effects were: sudden pain, scabs, herpes flare-up, and edema. The average score of pain during the procedure was 5,8+2,9. At the final assessment, the patients reported improvement of 80% and satisfaction of 85% (p<0.01). Pathological analysis showed a significant decrease of dysplasia (p=0.03) in spite of its presence in 84% of cases. There was no significant correlation between the level of dysplasia with either the subjective impression of clinical improvement (p=0.82) or with the patients’ final satisfaction (p=0.96).
|
PDT is effective in the treatment of actinic cheilitis, but it is associated with a significant level of pain. Due to the persistence of dysplasia, more research needs to be done in order to define the ideal number of sessions for the effective treatment of these lesions. |
3 |
|
Robinson JK 1989 |
To compare treatment with fluorouracil, chemical peeling, lip shave, or carbon dioxide laser treatment of actinic cheilitis |
Prospective study; n=40 |
Patients diagnosed with actinic cheilitis and patients who had either a basal cell or squamous cell carcinoma of the face, but not of the lip, that was resected by the Mohs' micro- graphic surgery method. |
Efficacy |
Forty patients with actinic cheilitis were treated with one of four modalities: topical fluorouracil, chemical peel with trichloroacetic acid, lip shave, or carbon dioxide laser ablation of the vermilion. Patients treated with lip shave or carbon dioxide laser ablation had no recurrence of the problem during 4 years. |
While the lip shave procedure offers the advantage of histologic examination of the specimen, the patients treated with the laser ablation had fewer postoperative complications. |
3 |
|
Rossini RC et al 2020 |
To evaluate local skin reactions (LSR) in patients with actinic cheilitis receiving ingenol mebutate (IM) gel 0.015% for self-application |
Interventional, prospective uncontrolled study; n=14 |
Patients with actinic cheilitis of the lower lip |
Tolerability |
All LSR had a complete resolution for up to 2weeks. The most common adverse events were burning sensation, angular cheilitis, and pain. There was an improvement of more than 80% in patients’ subjective evaluation. There was no statistically significant histopathological response since all patients remained with mild dysplasia. No reduction in the P53 expression was observed in the current study. |
Despite being a safe therapeutic method, the absence of histopathological or immuno- histochemical response suggests that clinical improvement may not be accompanied by histopathological cure for AC treated with IM. |
3 |
|
Smith KJ et al 2002 |
To review the results in patients who had been treated for actinic cheilitis with imiquimod cream. |
Retrospective study; n=15 |
Patients with biopsy-proven actinic cheilitis who had been treated with topical imiquimod 3 times weekly for 4 to 6 weeks |
Efficacy and tolerability |
All 15 patients showed clinical clearing of their actinic cheilitis at 4 weeks after discontinuation of the topical imiquimod. Sixty percent of the patients experienced a moderate to marked increased local reaction consisting of increased erythema, induration, and erosions or ulcerations, which in some cases continued through the period of therapy. |
Imiquimod appears to have a role in the treatment of actinic cheilitis. However, the dose and duration of therapy, as well as the long-term efficacy, need to be established; and local reactions are to be expected and may not improve during therapy. |
3 |
|
Sotiriou E et al 2010 |
To assess the clinical and histological long-term outcome in AC after two ALA-PDT sessions. |
Prospective uncontrolled study; n=40 |
Patients with histologically proven grade 1 and 2 AC |
Cosmetic outcome |
Of the 40 patients enrolled, 38 completed the study. Complete clinical response at 3 months was achieved in 26 patients. At 6 months, clinical and histological recurrence occurred in three patients and at 12 months, one more patient showed clinical and histological recurrence. At 18 months, overall clinical recurrence rate was 15.38% (4/26), while overall histological recurrence rate was 34.61% (9/26). Cosmetic outcome was rated as excellent in more than 80% of evaluated cases.
|
PDT represents a moderately effective treatment modality in AC. Optimization of treatment procedure and protocols is still needed for higher response rates to be achieved. Moreover, the high treatment cost should be given consideration. Further long-term follow-up studies are needed for assessment of clinical and histological very late recurrences that could be expected after PDT. |
3 |
|
Sotiriou E et al 2008 |
To evaluate the therapeutic efficacy of photodynamic therapy (PDT) for the treatment of actinic cheilitis |
Prospective uncontrolled study; n=10 |
Patients with biopsy-proven AC |
Efficacy, safety and cosmetic outcome |
Treatment was well tolerated. All patients reported a burning sensation during irradiation, but none of them asked to interrupt the procedure. The CR rate was 90% (nine of 10) while the non-CR rate was 10% (one of 10). Lesions with CR were biopsied for histological examination to verify the response. A single punch biopsy was taken of the site with the severest clinical signs pretreatment. The CR rate dropped to 80% (eight of 10) when taking into account the results of histological examination. Patients with clinical or histological non-CR received another treatment cycle. These patients showed, before treatment, diffuse, poorly demarcated lesions, while their pretreatment histological changes comprised mod- erate (grade 2) dysplasia. Significant reduction and relief of symptoms was reported by all patients. Cosmetic outcome was judged by the investigators as excellent in 60% of the patients and as good in 40%. The patients judged the outcome to be excellent in 80% and good in 20% All patients (100%) rated PDT as better than all previously received treatments. |
In conclusion, we believe that PDT using ALA is an effective and safe treatment option for AC, with the added advantage of excellent cosmesis, but with still unknown long-term cure rates. Further studies are needed to standardize optimal treatment protocols, to determine whether multiple treatment cycles can lead to complete clinical and histological cure and to compare the efficacy with conventional treatment modalities. Long-term follow-up is advised for assessment of recurrence. |
3 |
|
Sotiriou E et al 2011 |
To assess the clinical and histological long-term outcome as well as the safety and tolerability of sequential use of photodynamic therapy (PDT) and imiquimod in AC. |
Prospective uncontrolled study; n=34 |
Patients with histologically confirmed grade 1 and 2 AC |
Efficacy |
Of the 34 enrolled patients, 30 completed the study. Complete clinical response was achieved by 27 patients in 3 months. At 6 months, clinical and histological recurrence occurred in two patients, while at 12 months the complete clinical cure rate obtained was 80% and the histological complete cure rate was 73%. Treatment was well tolerated and adverse events were as expected and transient. |
Sequential use of PDT and imiquimod cream is of significant benefit for the treatment of AC. Further studies are needed to confirm the improved outcome using the combination treatment, to clarify the involved mechanisms and to optimize the therapeutic protocol. |
3 |
|
Vega-Memije ME et al 2002 |
To describe the clinicopathologic features and therapeutic results of 116 patients with actinic prurigo cheilitis seen over 11 years |
Retrospective study; n=116 |
Patients with actinic prurigo cheilitis treated in one center admitted consecutively from 1990 through 2000 |
Patients characterization and efficacy |
The study consisted of 42 male (36.2%) and 74 female (63.8%) patients, with a male to female ratio of 1:1.7. Age ranged from 9 to 82 years (mean, 27.9 years; standard deviation, 14.2). Thirty-two cases (27.6%) were found in which cheilitis was the only manifestation of this condition. Pruritus, tingling, and pain of the vermilion were recorded in 96 cases (82.7%). Typical histopathologic findings included in most cases the presence of acanthosis, spongiosis, basal cell vacuolation, ulceration with serohematic crust formation, edema of the lamina propria, lymphocytic inflammatory infiltrate with well-defined lymphoid follicles, and variable numbers of eosinophils and melanophages. Improvement of the symptoms was obtained in 112 cases (96.5%) with sun-protective measures and diverse anti-inflammatory agents. However, complete resolution of the labial lesions were more frequently achieved with the combination of topical steroids, thalidomide, and sun-protective measures (42.2%) as compared with topical steroid therapy plus sun-protection measures (16.3%; P < .005). |
Our findings confirm that lip lesions may appear as the only manifestations of this photodermatosis and that it has typical clinical and microscopic features and should therefore be considered a specific form of cheilitis. |
4 |
References
[290] Robinson, JK, Actinic cheilitis. A prospective study comparing four treatment methods., Arch Otolaryngol Head Neck Surg, 1989. 115 (7)(7): p. 848-52., https://pubmed.ncbi.nlm.nih.gov/2736096/
[291] Lai, M, Pampena, R, Cornacchia, L, Pellacani, G, Peris, K, Longo, C, Treatments of actinic cheilitis: A systematic review of the literature., J Am Acad Dermatol, 2020. 83 (3)(3): p. 876-887., https://pubmed.ncbi.nlm.nih.gov/31400450/
[292] Carvalho, MV, de Moraes, SLD, Lemos, CAA, Santiago Júnior, JF, Vasconcelos, BCDE, Pellizzer, EP, Surgical versus non-surgical treatment of actinic cheilitis: A systematic review and meta-analysis., Oral Dis, 2019. 25 (4)(4): p. 972-981., https://pubmed.ncbi.nlm.nih.gov/29908101/
[293] Salgueiro, AP, de Jesus, LH, de Souza, IF, Rados, PV, Visioli, F, Treatment of actinic cheilitis: a systematic review., Clin Oral Investig, 2019. 23 (5)(5): p. 2041-2053., https://pubmed.ncbi.nlm.nih.gov/31011833/
[294] Laws, RA, Wilde, JL, Grabski, WJ, Comparison of electrodessication with CO2 laser for the treatment of actinic cheilitis., Dermatol Surg, 2000. 26 (4)(4): p. 349-53., https://pubmed.ncbi.nlm.nih.gov/10759824/
[295] Lubritz, RR, Smolewski, SA, Cryosurgery cure rate of premalignant leukoplakia of the lower lip., J Dermatol Surg Oncol, 1983. 9 (3)(3): p. 235-7., https://pubmed.ncbi.nlm.nih.gov/6826879/
[296] Shah, AY, Doherty, SD, Rosen, T, Actinic cheilitis: a treatment review., Int J Dermatol, 2010. 49 (11)(11): p. 1225-34., https://pubmed.ncbi.nlm.nih.gov/20964646/
[297] Alamillos-Granados, FJ, Naval-Gías, L, Dean-Ferrer, A, Alonso del Hoyo, JR, Carbon dioxide laser vermilionectomy for actinic cheilitis., J Oral Maxillofac Surg, 1993. 51 (2)(2): p. 118-21., https://pubmed.ncbi.nlm.nih.gov/8426249/
[298] Dufresne, RG, Garrett, AB, Bailin, PL, Ratz, JL, Carbon dioxide laser treatment of chronic actinic cheilitis., J Am Acad Dermatol, 1988. 19 (5 Pt 1)(5 Pt 1): p. 876-8., https://pubmed.ncbi.nlm.nih.gov/3142939/
[299] Castiñeiras, I, Del Pozo, J, Mazaira, M, Rodríguez-Lojo, R, Fonseca, E, Actinic cheilitis: evolution to squamous cell carcinoma after carbon dioxide laser vaporization. A study of 43 cases., J Dermatolog Treat, 2010. 21 (1)(1): p. 49-53., https://pubmed.ncbi.nlm.nih.gov/19418331/
[300] Orenstein, A, Goldan, O, Weissman, O, Winkler, E, Haik, J, A new modality in the treatment of actinic cheilitis using the Er:YAG laser., J Cosmet Laser Ther, 2007. 9 (1)(1): p. 23-5., https://pubmed.ncbi.nlm.nih.gov/17506137/
[301] Gonzaga, AKG, de Oliveira, PT, da Silveira, ÉJD, Queiroz, LMG, de Medeiros, AMC, Diclofenac sodium gel therapy as an alternative to actinic cheilitis., Clin Oral Investig, 2018. 22 (3)(3): p. 1319-1325., https://pubmed.ncbi.nlm.nih.gov/28986686/
[302] Husein-ElAhmed, H, Almazan-Fernandez, FM, Husein-ElAhmed, S, Ingenol mebutate versus imiquimod versus diclofenac for actinic cheilitis: a 6-month follow-up clinical study., Clin Exp Dermatol, 2019. 44 (2)(2): p. 231-234., https://pubmed.ncbi.nlm.nih.gov/30242791/
[303] Lima, Gda S, Silva, GF, Gomes, AP, de Araújo, LM, Salum, FG, Diclofenac in hyaluronic acid gel: an alternative treatment for actinic cheilitis., J Appl Oral Sci 18 (5)(5): p. 533-7., https://pubmed.ncbi.nlm.nih.gov/21085813/
[304] Smith, KJ, Germain, M, Yeager, J, Skelton, H, Topical 5% imiquimod for the therapy of actinic cheilitis., J Am Acad Dermatol, 2002. 47 (4)(4): p. 497-501., https://pubmed.ncbi.nlm.nih.gov/12271290/
[305] Paolino, G, Cantoresi, F, Mercuri, SR, Cantisani, C, Clinical evaluation and efficacy of Imiquimod 3.75% cream for the treatment of actinic keratosis, pigmented basal cell carcinomas, and actinic cheilitis., Dermatol Ther, 2020. 33 (3)(3): p. e13356., https://pubmed.ncbi.nlm.nih.gov/32239714/
[306] Sotiriou, E, Apalla, Z, Koussidou-Erremonti, T, Ioannides, D, Actinic cheilitis treated with one cycle of 5-aminolaevulinic acid-based photodynamic therapy: report of 10 cases., Br J Dermatol, 2008. 159 (1)(1): p. 261-2., https://pubmed.ncbi.nlm.nih.gov/18489592/
[307] Sotiriou, E, Apalla, Z, Chovarda, E, Panagiotidou, D, Ioannides, D, Photodynamic therapy with 5-aminolevulinic acid in actinic cheilitis: an 18-month clinical and histological follow-up., J Eur Acad Dermatol Venereol, 2010. 24 (8)(8): p. 916-20., https://pubmed.ncbi.nlm.nih.gov/20028448/
[308] Berking, C, Herzinger, T, Flaig, MJ, Brenner, M, Borelli, C, Degitz, K, The efficacy of photodynamic therapy in actinic cheilitis of the lower lip: a prospective study of 15 patients., Dermatol Surg, 2007. 33 (7)(7): p. 825-30., https://pubmed.ncbi.nlm.nih.gov/17598848/
[309] Chaves, YN, Torezan, LA, Lourenço, SV, Neto, CF, Evaluation of the efficacy of photodynamic therapy for the treatment of actinic cheilitis., Photodermatol Photoimmunol Photomed, 2017. 33 (1)(1): p. 14-21., https://pubmed.ncbi.nlm.nih.gov/27864997/
[310] Ribeiro, CF, Souza, FH, Jordão, JM, Haendchen, LC, Mesquita, L, Schmitt, JV, et.al. Photodynamic therapy in actinic cheilitis: clinical and anatomopathological evaluation of 19 patients., An Bras Dermatol 87 (3)(3): p. 418-23., https://pubmed.ncbi.nlm.nih.gov/22714758/
[311] Radakovic, S, Tanew, A, 5-aminolaevulinic acid patch-photodynamic therapy in the treatment of actinic cheilitis., Photodermatol Photoimmunol Photomed, 2017. 33 (6)(6): p. 306-310., https://pubmed.ncbi.nlm.nih.gov/28703320/
[312] Radakovic, S, Dangl, M, Tanew, A, 5-Aminolevulinic acid patch (Alacare) photodynamic therapy for actinic cheilitis: data from a prospective 12-month follow-up study on 21 patients., J Eur Acad Dermatol Venereol, 2020. 34 (9)(9): p. 2011-2015., https://pubmed.ncbi.nlm.nih.gov/31999856/
[313] Yazdani Abyaneh, MA, Falto-Aizpurua, L, Griffith, RD, Nouri, K, Photodynamic therapy for actinic cheilitis: a systematic review., Dermatol Surg, 2015. 41 (2)(2): p. 189-98., https://pubmed.ncbi.nlm.nih.gov/25627629/
[314] Levi, A, Hodak, E, Enk, CD, Snast, I, Slodownik, D, Lapidoth, M, Daylight photodynamic therapy for the treatment of actinic cheilitis., Photodermatol Photoimmunol Photomed, 2019. 35 (1)(1): p. 11-16., https://pubmed.ncbi.nlm.nih.gov/30066408/
[315] Andreadis, D, Pavlou, A-, Vakirlis, E, Anagnostou, E, Vrani, F, Poulopoulos, A, et.al. Daylight photodynamic therapy for the management of actinic cheilitis., Arch Dermatol Res, 2020. 312 (10)(10): p. 731-737., https://pubmed.ncbi.nlm.nih.gov/32266532/
[316] Choi, SH, Kim, KH, Song, KH, Efficacy of ablative fractional laser-assisted photodynamic therapy for the treatment of actinic cheilitis: 12-month follow-up results of a prospective, randomized, comparative trial., Br J Dermatol, 2015. 173 (1)(1): p. 184-91., https://pubmed.ncbi.nlm.nih.gov/25400009/
[317] Sotiriou, E, Lallas, A, Goussi, C, Apalla, Z, Trigoni, A, Chovarda, E, et.al. Sequential use of photodynamic therapy and imiquimod 5% cream for the treatment of actinic cheilitis: a 12-month follow-up study., Br J Dermatol, 2011. 165 (4)(4): p. 888-92., https://pubmed.ncbi.nlm.nih.gov/21916880/