FormalPara Key Summary Points

The classical management of melanoma is surgery, but it can be challenging because of several factors, such as age, body area, lesion size, among others.

The purpose of this systematic review is to assemble current evidence on the treatment of non-metastatic melanoma with topical imiquimod.

A total of 87 studies covering 1803 lesions were included in this systematic review, of which 49 were case reports, 16 were retrospective analysis, 13 were open label trials, six were case series; one was a controlled randomized trial, one a randomized trial, one was a single-arm phase III trial. Because of the high number of low-evidence studies, the overall risk of bias was high.

Of the 1803 lesions, 1133 (62.8%) cleared after the treatment and 107 lesions relapsed. The efficacy of imiquimod cream in melanoma in situ and lentigo maligna melanoma was demonstrated, but uniform evidence regarding the modalities of treatment is lacking.

Introduction

Melanoma is a malignant tumor originating from melanocytes. It can involve every tissue where there are melanocytes (cutis, mucosae, conjunctiva, uvea, meninges, etc.), but the cutis is the most frequently affected area [1, 2]. For example, cutaneous melanoma (CM) is classified according to assessment of the infiltration of the melanoma in situ (MIS), whether atypical melanocytes are confined to the epidermis, and whether there is invasive melanoma in which cancerous cells invade dermis and other structures. In turn, invasive melanoma can be classified into four clinic-pathological subtypes: superficial spreading melanoma (SSM), nodular melanoma (NM), lentigo maligna melanoma (LMM), and acral lentiginous melanoma (ALM) [1, 3].

Lentigo maligna (LM) and LMM represent a continuous spectrum. LM is a slow-growing melanoma in situ that appears mostly in UV-exposed regions, such as the face [4]. LMM is an invasive melanoma with LM elements and the metastatic potential of melanoma [5]. The classic management of non-invasive melanoma is surgery, but this approach can be challenging in some cases or non-realizable. For example, the lesion may be close to important anatomical structures, show unclear margin, or be very large; in these situations, reaching the surgical radicality can be difficult [6]. Furthermore, many patients are elderly with comorbidities, and the surgical approach may not be the best choice [7, 8]. In these situations, a non-surgical treatment, such as radiotherapy [9], cryotherapy [10], laser [11], or topical imiquimod [12], may be useful. At the present time, topical imiquimod is used to treat LM, MIS, and, more rarely, LMM as an off-label therapy [13,14,15,16,17]. The registered use is for adults affected by small non-nodular basal cell carcinomas, actinic keratoses, and warts on the anogenital area [18].

High-quality evidence supporting the role of imiquimod as primary therapy is lacking, but a number of retrospective analyses and trials have demonstrated how this drug can be a good alternative to surgery. This option could be considered in selected cases not eligible for surgery or radiotherapy, or for incompletely excised tumors. Another use could be as neoadjuvant, adjuvant, or complementary therapy [7, 19]. However, topical imiquimod should be chosen with caution for younger patients affected by LM because this patient population has a higher lifetime risk of developing LMM than older patients (≥ 65 years) [20].

Imiquimod is a synthetic drug belonging to the imidazoquinolone family [21] and initially developed as an antiviral [22, 23], although its antiviral action has never been demonstrated. In contrast, the antitumoral activity of imiquimod was discovered in pre-clinical models [24]. Further, its chemical properties, such as hydrophobiocity and small size (Mr = 240.3) allow imiquimod to penetrate the epidermal barrier, making it a perfect molecule for topical use [25]. Imiquimod stimulates the innate immune system, acting primarily on cutaneous dendritic cells (DC) that are able to respond to low concentrations of drugs [26,27,28,29]. This activation of DC activation seems to be mediated by the interaction between imiquimod and Toll-like receptors (TLRs) 7 and 8, resulting in activation of nuclear factor-kappa B (NF-κB) and the consequent production of pro-inflammatory cytokines, such as interferon alpha (IFNα), tumor necrosis factor alpha (TNFα), and other important cytokines with a strong Th1-weighted cellular response. The outcome is an activation and immigration of cytotoxic T cells. Imiquimod also induces 2′5′-oligoadenylate synthase with subsequent stimulation of NK cells and the induction of perforin in cytotoxic T cells. Both of these mechanisms may increase the antitumoral activities of imiquimod [24]. Imiquimod can also bind the adenosine receptor (AR). When activated, AR can suppress the translation of pro-inflammatory cytokines, thereby downregulating the immune response. Imiquimod, by blocking AR, impedes a negative feedback mechanism that limits inflammation, improving the immunity response to cancer [28, 29]. Finally, the topical use of imiquimod increases the expression of cell death receptor CD95 (Fas) 57 and decreases the expression of antiapoptotic protein with an increase of tumor cell apoptosis. This pro-apoptotic activity can be direct or indirect, with the former effect depending on drug concentration and the latter appearing to be mediated by TLR activation [25].

The adverse effects associated with imiquimod are primarily due to its mechanism of action. The most common adverse effects are local erythema, burning, edema, and crusts [30]. The development of alterations in skin pigmentation, such as post-inflammatory hyper and hypopigmentation, are also possible [31]. In their study, Di Bartolomeo et al. observed the formation of perifollicular blue gray dots after 12 weeks of treatment with imiquimod 5% [32]. These authors speculated that these structures corresponded to dermal melanophages activated by the imiquimod-related inflammatory process [33]. Hypopigmentation or vitiligo-like depigmentation may also be observed. The latter, unlike the classic forms of vitiligo, can show spontaneous repigmentation [34]. Furthermore, halo nevi could occur in areas outside the sites of imiquimod cream application [34, 35]. Moreover, some patients can experience constitutional symptoms due to cytokine release, but these are self-limiting [20].

It is necessary to pay attention to the use of imiquimod near sensitive structures such as the eyes. Murchinson et al. reported the use of imiquimod 5% on a lesion near the right eye, with subsequent chemosis of the lateral palpebral conjunctiva, a decrease of visual acuity, diffuse punctate keratopathy, and corneal edema [36]. All of these adverse effects were resolved by interrupting the topical treatment with imiquimod and using petroleum jelly, cool compresses, and ophthalmic erythromycin. After 1 month, a small crusting area remained on the cheek, without residual melanosis. The visual acuity was 20/30 on the right eye with a clear cornea and without chemosis. In another study, Conforti et al. [37] treated a LM close to the conjunctiva without severe side effects, using a combination of topical steroid and hyaluronic acid eye-drops. These authors concluded that conjunctival inflammation can be easily treated without permanent ocular side effects and for that reason the use of imiquimod 5% is safe in the periorbital area. On the other hand, the corneal edema caused by imiquimod 5% could induce fibrosis and lymphohistiocytic infiltrate with a consequent compression of lymphatic vessels and the development of lymphoedema that can potentially persist for years, as reported by Tio et al. [31]. Therefore, in order to limit adverse effects, it is important to adapt the number of weeks of imiquimod application based on the patient’s inflammatory reaction [31] .

Here we report the results of a systematic review that was initiated in order to assemble current evidence on the treatment of non-metastatic melanoma with topical imiquimod, to better understand the modalities, and to propose a non-invasive option in patients who are not eligible for surgery.

Materials and Methods

This systematic literature review was conducted using PubMed/MEDLINE and Cochrane Library as primary sources. All articles in these databases up to March 2023 were considered, with the last search date being 16 March 2023. The main search terms were “imiquimod” combined with “lentigo maligna” and “melanoma” with the command AND.

All articles in English on the efficacy of imiquimod for the treatment of LM, MIS, and LMM in human subjects were included. Articles identified in the search on invasive melanoma (except for LMM), melanoma metastasis, and non-melanoma skin cancer were excluded, as were articles on molecular and in vitro studies. Previous reviews were also excluded, but the respective bibliography of each identified review was used to identify articles that may have been missed in the primary search. Commentaries were also excluded.

Articles were identified, screened, and extracted for relevant data in accordance with the PRISMA guidelines [38] by two reviewers who worked independently. The articles included case reports, case series, open label trials, retrospective analyses, clinical trials, and randomized studies. Case reports and old references were included because of the suboptimal evidence on the topic.

For each study the following items were considered: epidemiologic features of patients; diagnosis (LM/MIS/LMM); number of treated lesions; localization of lesions; diagnostic method (histology/clinical); protocol of treatment; margins of the lesions included in treated area; response after the treatment, specifying the verification method (complete/partial/none; histology/clinical/other); time of long-term follow-up (as range or average time); and number of relapses, specifying the verification method (histology/clinical/other) at the time of the long-term follow-up. Missing data were classified as “not recorded” or “not applicable.”

The quality of the enrolled studies was appraised using the revised Cochrane risk-of-bias tool for randomized controlled trials (RCTs) [39] and the overall risk of bias for each study was judged as low, high, or of some concern.

This systematic review is based on previously conducted studies and does not contain any studies with human participants or animals performed by any of the authors.

Results

A total of 87 studies covering 1803 lesions treated with imiquimod cream were included in this review. The selection process is shown in Fig. 1.

Fig. 1
figure 1

Flow chart of the selection of the studies included in the review

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The main features of the selected studies are reported in Table 1. Of the selected studies, 49 were case reports, 16 were retrospective analysis, 13 were open label trials, six were case series; one was a RCT, one a randomized trial, one a single arm phase III trial. Because of the high number of low-evidence studies, the overall risk of bias resulted high.

Table 1 Results of literature search
Full size table

In the included studies, age was expressed as range, mean, or median, depending on the individual study. A median age was not always available. The lowest and highest age was 33 [82] and 96 years [96], respectively; the lowest and highest mean age was 60 [43] and 80 years [113], respectively. Most of the patients selected for imiquimod treatment were elderly and, presumably, with comorbities. The latter was often not reported in the studies analyzed. Some young patients were also selected for imiquimod treatment, especially where difficulties were encountered with a surgical approach regarding body localization of the lesion, i.e., genital area [16, 94].

In all cases the initial diagnosis of LM/MIS/LMM was histologically confirmed through punch biopsies, partial excision, or excision with positive margins, with one exception [63] which was confirmed with videodermoscopy. Only four studies reported on the treatment of LMMs [88, 101, 110, 112, 117].

The majority of the lesions were located on the head/neck area; the remaining body areas treated included limbs, extremities, back, thorax, and genitals. The lesions treated were not only the first diagnosis, but also relapses and results of incomplete previous surgeries.

In 55 studies, imiquimod 5% was used as monotherapy in the primary treatment; only in one study was imiquimod 3.75% introduced into the treatment regimen [115]. In most cases, the topical treatment was applied once/daily; the exceptions were ten cases [12, 41, 59, 64, 87, 90, 97, 103] where an increased dosage per day was applied. In four cases [17, 59, 90, 97], the authors of the study required patients to apply imiquimod cream in occlusion. The ranges of number of days/weeks of treatment and the total duration of the treatmetn regimen were extremely variable (1–7 days/weeks and 1–60 weeks, respectively) and depended on the body area and the tolerability of the patient, with differences among patients in the same study as well. Some authors reported the number of patients who did not complete the treatment [43, 75, 77, 85] and/or who had a therapeutic break during the treatment protocol [16, 17, 50, 56, 68, 86, 93].

In six studies [44, 60, 75, 80, 93, 99], imiquimod was used as neoadjuvant therapy before the surgical excision, and in 11 studies [34, 45, 52, 54, 56, 83, 84, 86, 101, 105, 109] imiquimod was used after the surgical, possibly serial, excision with partial or with positive margins, respectively as complementary or adjuvant therapy (in some cases not all the population of the study did the surgical procedure). In one study [112], monotherapy and adjuvant therapy were compared. In an another study [113], adjuvant, complementary, and monotherapy were compared. Finally, in one study [117] adjuvant and monotherapy were compared.

In ten studies [60, 69, 86, 95, 96, 99, 107, 109, 114, 117], topical retinoids (tazarotene, tretinoin) were added to the topical treatment with imiquimod with different modalities (before/after/at the same time of the treatment or only in case of insufficient inflammatory response). In one case [77], the neoadjuvant therapy with imiquimod only was compared to neoadjuvant therapy with imiquimod + tazarotene. In three [58, 59, 112] and two studies [81, 91], imiquimod was associated with cryotherapy and with laser therapy, respectively.

In 30 studies, the application of imiquimod was extended beyond the lesions with margins of between 0.5 and 2 cm. In two studies [49, 101] on LM of the cheek, the treatment was applied onto the whole cheek. In four cases [59, 72, 90, 102], the treatment was applied only on the lesion, excluding the margins. In all other studies, these data were not reported.

In 23 studies, clearance after the treatment was checked with a clinical and/or dermoscopic examination; in the other studies, the patient populations were re-biopsied, at least partly, depending on the patient’s consent. In total, 1133 out of 1803 (62.8%) lesions were reported to be cleared after the treatment, taking account that not all the patients completed the treatment and that, in some cases, patients who did not complete the treatment were included in the final analysis. Of the 1133 lesions, histological clearance was achieved in 645 (56.9%) lesions and clinical clearance only was achieved in 490 (43.2%) lesions. For 34 lesions, the initial clearance was tested with the confocal microscopy [98, 119] and (1 case) with videodermoscopy [63].

In most cases the long-term follow-up was mainly clinical, with time ranges extremely variable (0–17.1 years [109]). In two studies, the long-term follow-up was realized with reflectance confocal microscopy [92, 98] and in 22 studies it was realized with biopsy and histological examination. Seventy-one studies reported data on recurrence; in total, 107 lesions relapsed.

Seventeen studies [16, 53, 62, 63, 68, 74, 80, 90, 97, 98, 101, 103, 108, 115,116,117, 119] mentioned the importance of the (video)dermoscopy for diagnosis and follow-up and to guide the biopsies. In addition, seven studies [74, 82, 92, 98, 100, 118, 119] mentioned or used the reflectance confocal microscopy.

Finally, in two studies [90, 109], the authors made a disease-free survival analysis.

Discussion

Existing data suggest that imiquimod has a therapeutic effect on non-invasive melanoma and LMM. However, as mentioned in the “Introduction”, the level of evidence is generally low and the patient populations of individual studies are small. The largest patient population was described in the study by Donigan et al. [99], which was a retrospective medical record review of 334 patients (mean age 67 years) with 345 biopsy-confirmed LM tumors, of whom 294 were recurrences. These patients were treated with neoadjuvant 5% imiquimod cream for a mean of 2.5 months, with or without 0.1% tazarotene gel, prior to conservatively staged excisions beginning with 2-mm margins. A mean of 1.2 surgical stages with a mean margin of 3.5 mm were required to clear the tumor. Residual LM was present in 18% of specimens cleared with stage 1. Thirty-two patients had a complete clinically response to imiquimod prior to staged excision. Thirty-seven patients (39 tumors) were lost to follow-up, and seven of them died. The mean length of follow-up for the remaining 297 patients was 5.5 years. There was a recurrence rate of 3.9%, with a mean time to recurrence of 4.3 years.

Also, there are no comparative studies between the classic surgical treatment, or radiotherapy, and treatment with imiquimod. As previously stated, the main disadvantage of this systematic review is the inclusion of several case reports/series, which make the risk of bias higher. However, we expressly applied broad inclusion criteria in order to include as many studies as possible with the aim to represent the state-of-the-art of this topic and its evolution during the years.

Despite the limited number of studies, imiquimod treatment appears in several international guidelines for the management of LM, such as European Association of Dermato Oncology (EADO) [122], American Academy of Dermatology (AAD) [123], and Italian Association of Medical Oncology (AIOM) [124]. In particular, in the EADO and AIOM guidelines, imiquimod 5% is proposed as a potential alternative to surgery in patients not eligible for radiotherapy or surgery. In the AAD guidelines, imiquimod 5% treatment is proposed as second-line treatment in the primary or adjuvant setting (strength of recommendation B, level of evidence II/III). Moreover, in a 2018 survey sent to the members of European Association of Dermatologists and Venereologists (EADV), the most common treatment for LM patients was surgery (97.6% of respondents), followed by topical imiquimod (49.7% of respondents), with the latter treatment suggested predominantly for elderly patients [7].

The first aspect to consider when considering topical imiquimod for the treatment of non-invasive melanoma is the extreme heterogeneity in the protocols, the extension of the treatment to margins, the modality of verifying the clearance, and the follow-up. In addition, the lesions treated and the characteristics of the patients in the studies were very heterogeneous. In those studies with more than one patient, LM/MIS/LMM, first diagnosis/relapses, and patients with/without previous treatment were not distinctly considered. Because of the absence of a stratification of the groups, our final analysis is indicative only, but it cannot be precise and conclusive concerning the modality of the treatment. The same limitation holds for the time of follow-up, which was often non-uniform among patients of the same study with very wide time ranges. For this reason, we are unable to draw conclusions on the time of relapse and its association with patients, the type of lesion, and the treatment protocol.

Another aspect to consider is the response rate to the treatment. First, it is necessary to note that most of the non-responders were reported in studies with a large sample, whereas this was rarer for case reports and case series, indicating a bias of selection. Second, in most studies, the response was assessed as the level of inflammation, implementing the dosage, or adding other therapies (topical retinoids, cryotherapy) in the case of insufficient response. These variables explain, at least partially, the variability of the treatment regimen.

The topical application of imiquimod was generally well tolerated by patients, and the irritant adverse effects rarely led to a premature interruption of the therapy. However, strict follow-up of the patient is mandatory to adjust the dosage and ensure patient compliance to the treatment and the clearance of the lesion. In summary, imiquimod therapy must be personalized for the patient being treated. Also, the total duration of the treatment and its implementation from the first appearance of inflammation, as well as the need for a post-treatment biopsy remain unclear. With regard to the latter latter aspect, a recurrent issue involves the residual hyperpigmentation at the end of the treatment, linked to residual neoplastic cells or to melanophages and melanin. Indeed, this clinical aspect makes it difficult to assess an incomplete clearance and often leads to a post-treatment surgery. The actual evidence does not lead to avoidance of a final biopsy or surgery in these cases, but some authors raised the importance of non-invasive methods, such as dermoscopy [16, 53, 62, 63, 68, 74, 80, 90, 97, 98, 101, 103, 108, 115,116,117, 119] and confocal microscopy [74, 82, 92, 98, 100, 118, 119], with the latter preferable in terms of histopathological criteria [121] but less available in daily practice. Treatment with imiquimod is non-invasive, but at the present time an initial biopsy to ensure that the melanoma is non-invasive is mandatory and a biopsy when there is suspicion of partial/absent response or relapse are preferred.

One of the most crucial aspects in studies concerns recurrence. In particular, the timing of the follow-up varies among studies and among patients of the same study. Furthermore, the data on relapse in these studies were not always specified. Currently available data do not allow any evaluation of the relapse rate.

Conclusions

The efficacy of local imiquimod cream to treat non-invasive melanoma, and LMM in some cases, has been demonstrated, but the heterogeneity of the included studies precludes the drawing of a firm conclusion. In addition, uniform evidence concerning the modalities of treatment is lacking. At the present time, this kind of therapy cannot substitute for the classical surgical treatment, but it can be considered for the treatment of patients of advanced age, systemic diseases that contraindicate surgical procedures, large lesions, and lesions occurring in difficult anatomic locations. Also, imiquimod can be associated with the surgical procedure as neoadjuvant, adjuvant, or complementary treatment to avoid large flaps and skin grafts. An accurate post-treatment assessment is mandatory, including clinical-dermoscopic examination, examination with the confocal microscopy, if possible, and a histologic follow-up, if deemed necessary. Identification of eligible patients for which this non-invasive treatment can represent a better option compared to the conventional treatments, the protocol, and the timing of the follow-up remain the main challenges for the future.