Reports

This report is based on medical evidence presented at sanctioned medical congress, from peer reviewed literature or opinion provided by a qualified healthcare practitioner. The consumption of the information contained within this report is intended for qualified Canadian healthcare practitioners only.

21st World Congress of Dermatology

Buenos Aires, Argentina / September 30-October 5, 2007

Non-melanoma skin cancer (NMSC) exceeds all other malignancies in much of the world today. Directly linked to excessive sun exposure, the incidence of both basal-cell and squamous-cell carcinoma (BCC/SCC) has been increasing over the past several decades. In the general population, a history of sunburns, particularly during childhood, is cited as a key risk factor for NMSC, but exposure to artificial sources of ultraviolet (UV) rays from tanning booths has likely contributed to the increasing incidence of NMSC as well. The success of organ transplantation, which by necessity relies on lifelong immunosuppression, is a significant risk factor for NMSC, especially SCC, particularly in kidney transplant recipients, where the incidence of NMSC is disturbingly high.

Removal of both BCC as well as precancerous actinic keratoses (AK) can require relatively invasive modalities including cryotherapy, surgical excision, Mohs micrographic surgery, photodynamic therapy, electrocoagulation or electrodessication. Depending on where the lesions are located, these approaches are not always feasible. SCC lesions can be more invasive and they can metastasize, thus necessitating aggressive surgical management, radiation therapy or both.

The approval of topical imiquimod 5% for AK and certain types of BCCs has revolutionized the ease with which physicians may now treat certain skin lesions. As described by Dr. Anthony Gaspari, Professor of Dermatology, University of Maryland, Baltimore, imiquimod activates antigen-presenting cells, thereby triggering cytokine production and amplifying T-lymphocyte-mediated immune responses. “The cellular receptors of imiquimod…are toll-like receptors [TLRs] 7 and 8,” he explained, “and these two receptors are part of a larger family of TLRs that are a critical component of innate immunity and which evolved to detect dangerous bacterial, viral, fungal and parasitic infections.” Because a number of cell types in the skin express either TLRs or receptors for cytokines induced by imiquimod, “this agent has broad-reaching direct and indirect effects in the skin as well as the related skin immune system,” Dr. Gaspari added.

Corroborative Evidence

The fact that these multiple mechanisms of action have anti-tumour properties was supported by a number of studies presented here, including one under lead author Dr. Donald Tillman, Great Plains Dermatology, Hays, Kansas. In this series, 90 patients with histologically confirmed BCC underwent curettage first to remove all remaining tumour followed by electrodessication primarily applied to secure hemostasis. “Ten days following curettage, imiquimod 5% cream was applied to the treated area once daily, five days a week, for six weeks,” the researchers noted. The majority of the BCCs treated in this series were nodular (61%) at a mean size of 1.01 cm.

At a mean follow-up of 48 months, researchers reported a 96% clearance rate. All patients experienced some reaction to the cream at the treatment site, ranging from mild to severe. Still, the authors concluded that their 48-month clinical experience shows treatment is “a safe and effective method” to enhance curettage and electrodessication for the treatment of BCC.

The same researchers also reported on their experience treating SCC. As they noted, since SCCs typically exist in transition areas in patients who have multiple AKs, the margin for clearance may be blurred if physicians try to remove the SCC through other modalities. All SCC lesions were again subjected to curettage followed by electrodessication and imiquimod 5% cream 10 days later, once a day, five days a week for six weeks.

At 48 months, a 95% clearance rate was achieved in this series of 99 biopsy-proven, low-risk SCCs and all patients tolerated the cream, the most common complaints being mild burning and itching at the application site.

In a separate study, lead author Dr. Elena Campione, Department of Dermatology, Tor Vergata University of Rome, Italy, reported that the clinical remission initially achieved using imiquimod cream 5% for five days a week up to 16 weeks on either primitive SCC (two patients), recurrent SCC (one patient) or Bowen’s disease (two patients) was maintained for up to two years after patients underwent treatment. “No side effects were observed,” the authors noted, “and imiquimod may be considered as a useful treatment in patients affected by SCC not eligible for surgery.”

Immune-modulating Effects

The immune-modulating effects of imiquimod 5% have broader applicability outside of NMSC including the treatment of lentigo maligna, a form of melanoma in situ that often requires wide surgical margins into normal skin to eradicate. “If left untreated, lentigo maligna may progress to invasive melanoma as well,” noted Drs. William Gerstein and A. Kevin Watters, Division of Dermatology, MUHC-Montreal General Hospital, Quebec. They had previously reported their experience in two patients with lentigo maligna whom they had treated with imiquimod and this year, they presented a follow-up report on these two patients plus three additional patients who had either giant or large lentigo maligna on the face and scalp and who were similarly treated with imiquimod.

All patients were treated with the cream for five days a week for up to three months. Following an initial marked inflammatory reaction to imiquimod, “we observed a long clinical and histological remission in these patients, with no evidence of recurrence or invasion at long-term follow-up at up to 62 months,” authors reported, “and our data provide early insight into the use of topical immunostimulatory agents as an alternative to surgery in patients with this type of virtually inoperable cutaneous neoplasm.”

The success of the Montreal group was echoed by investigators under lead author Dr. Emma Craythorne, Department of Dermatology, Royal Victoria Infirmary, Newcastle-upon-Tyne, UK, who described their experience using imiquimod in eight patients with recurrent or difficult-to-treat lentigo maligna of the head and neck. “Patients were instructed to apply the cream to the pigmented area and to a minimum 1-cm margin around the pigmented area once a day, five days a week, for six weeks,” they explained. Intriguingly, seven patients developed a brisk inflammatory response to the cream and of these, six had clinical resolution of their lesion. Indeed, the appearance of a brisk inflammatory response to treatment appears to be necessary, as when it was absent, lesions did not resolve. On stopping application of a concurrent barrier cream, however, retreatment with imiquimod did lead to clinical resolution of the lesion.

During an average follow-up of 31.5 months, none of the responders had a clinical recurrence, the authors added. “Our study shows that imiquimod is potentially an excellent non-surgical treatment for lentigo maligna, particularly in those patients who present with large or recurrent lesions on the head and neck,” the authors concluded, adding that an inflammatory response appears to be a prerequisite for treatment success with imiquimod.

As observed by researcher Dr. Claas Ulrich, Skin Cancer Center Charité, Berlin, Germany, organ transplant recipients are at an extremely high risk to develop AK and SCC because of immunosuppressive therapy. When lesions develop, they are often more aggressive and become more invasive earlier compared to similar lesions that occur in patients with intact immune systems. The effectiveness of three different topicals, including imiquimod cream 5%, in the prevention and treatment of AK, BCC and SCC in transplant recipients has now been evaluated. The other two compounds evaluated in separate studies included a highly protective liposomal sunscreen and 3% diclofenac in 2.5% hyaluronic acid gel.

As presented by Dr. Ulrich, results from the liposomal sunscreen study showed that the incidence of AK was markedly reduced in transplant recipients and no newly developed invasive SCCs were noted. In the placebo-controlled imiquimod study, no severe local side or systemic effects were observed and clinical clearance rates were comparable to those reported in non-immunosuppressed patients. In the diclofenac/hyaluronic acid study, no systemic side effects were observed and efficacy rates approached those reported in the non-transplant population. “Since the numbers of disease-related or iatrogenetically immunocompromised patients will steadily increase worldwide, these results will be of importance for upcoming skin cancer challenges in the field,” Dr. Ulrich concluded.