Alternative Therapies: Topical Treatment and Injections
Mariam Totonchy and Jonathan Scott Leventhal
Topical and intralesional agents have an important role in the treatment of patients with melanoma, including in situ, locoregional, and unresectable disease. These therapies can be administered to accessible melanoma lesions, with the potential to induce an immunological response. The benefits of these therapies include the ability to treat patients who are not surgical candidates due to widespread, in-transit metastases or patients with positive histologic margins after surgical excision. In addition, these agents offer alternative options to palliate those with poor functional status or with contraindications to systemic therapy. Skin-directed therapies with high concentrations of antitumoral agents have been shown to result in complete or partial responses with minimal systemic toxicity. In addition, an antitumoral immune response referred to as the “bystander effect” may potentiate the usefulness of these agents. This section will review the most contemporary topical and intralesional therapies used in the treatment of melanoma.
Imiquimod is a member of the imidazoquinoline family of small nucleoside-like molecules that has both antitumor and antiviral properties. In the United States, it is approved for the treatment of actinic keratosis, external genital warts, and superficial basal cell carcinoma. Imiquimod acts as a pro-inflammatory immunomodulator that interacts with Toll-like receptor 7 on plasmacytoid dendritic cells and increases levels of interferon-alpha, interleukin-12, and type-1 T helper cells of the adaptive immune system (1–3). Imiquimod also activates the innate immune system by increasing production of several cytokines including interferon-alpha, tumor necrosis factor alpha, and interleukin-6 (1).
In recent years, there has been increasing interest in the use of imiquimod as a potential noninvasive adjuvant or neoadjuvant agent for melanoma in situ. While surgical resection remains the gold standard of therapy, imiquimod is an attractive agent for patients with noninvasive disease who are not surgical candidates, have positive margins after excision, or those with a surrounding field defect of atypical melanocytic proliferation (4). In addition, it has been used as a second-line treatment for inoperable disease either due to the size or location of the melanoma, age and comorbidities of the patient, and inability to achieve histologic clearance by surgery alone.
An initial case report in 2000 demonstrated the use of imiquimod for treatment of lentigo maligna (in situ phase of lentigo maligna melanoma) in a man who declined surgical excision of a large lesion on his scalp (5). He was treated with imiquimod 5% cream for 7 months (daily to three times weekly) and had a complete histologic and clinical clearance without recurrence at 9-month follow-up (5). Since then, there have been multiple studies showing safe and efficacious use of imiquimod for melanoma in situ (4,6–9). While treatment frequency and length of time varies between studies, the typical regimen is daily application of imiquimod 5% cream for 12 weeks (10).
One retrospective review of 48 patients treated with imiquimod 5% cream for facial lentigo maligna showed a 77% response rate, with no clinical or histologic evidence of disease at 4 to 6 months after treatment (11). Patients were followed for a mean of 49 months with no evidence of recurrence (11). Another systematic review of 347 lentigo maligna tumors treated with topical imiquimod demonstrated a 78% clinical and 76% histologic clearance rate (8). Other reviews cite an observed or calculated response rate of 67% to 93% (9,12–14).
It is important to monitor patients closely after treatment with topical imiquimod for disease recurrence. A prospective study of 89 patients found a recurrence rate of 18%, with a median time to relapse of 1.89 years (15). In addition, there are documented cases of disease progression from in situ to invasive melanoma following treatment with imiquimod (11–13,16,17). This may be the result of treatment failure or undiagnosed invasive disease prior to initiation with topical therapy. For these reasons, complete biopsy is necessary to exclude invasive disease prior to therapy and scouting biopsies should be performed 6 to 8 weeks after cessation of therapy to confirm histologic clearance. Physicians must consider the risk of sampling error in post-treatment biopsies and follow patients closely.
Adjuvant treatment of melanoma in situ with topical imiquimod has been used after surgical excision for cases with persistently positive margins (18,19). A retrospective review of 22 patients treated with imiquimod for residual melanoma in situ following standard surgical excision found a 95% (21/22) clinical and histologic response rate (20). There was no evidence of recurrence in responders at a mean follow-up time of 2 years. In addition, the use of imiquimod as neoadjuvant therapy prior to surgical excision has been studied in an attempt to reduce the size of the operative defect (21). A retrospective study found a 75% (30/40) histologic clearance rate following 12 weeks of treatment with imiquimod in 40 patients with lentigo maligna prior to surgical excision (22).
In addition to melanoma in situ, imiquimod has also been used for treatment of locally advanced metastatic melanoma both as monotherapy and as combination therapy with cryotherapy, 5-fluorouracil, topical retinoids, intralesional IL-2, intralesional Bacille Calmette-Guérin (BCG), and radiation therapy with varying degrees of success (23–29). Figures 13.1 A and B illustrate an elderly patient with recurrent melanoma (0.35-mm Breslow depth) of the right shin who declined surgical therapy and was treated with topical imiquimod under the occlusion of saran wrap. She was treated daily for 5 days a week and had clinical resolution of the nodule after 3 months of treatment.
Treatment with imiquimod is generally well tolerated. The main adverse event is local skin inflammation, including pain, erythema, edema, and ulceration. Systemic symptoms such as headaches and myalgias are less common. Importantly, there is a correlation between degree of inflammation and treatment response, suggesting its potential use as a prognostic factor (9,11,15,20). One study found that the majority of nonresponders (9/11) showed no clinical evidence of inflammation, whereas among responders, only 6/37 did not mount an inflammatory response (11). For patients who do not display an appropriate inflammatory response to therapy, the addition of a topical retinoid has been shown to enhance the degree of inflammation (21). In addition, application under occlusion may increase penetrance of the imiquimod. There is a need for additional prospective studies monitoring longevity of response to imiquimod in MIS patients.
Other Topical Agents
While imiquimod is the mainstay topical agent used in the treatment of melanoma in situ or in-transit metastases, several case reports and series document the use of topical 5-fluorouracil, azelaic acid, and the contact sensitizer diphencyprone (DPCP) for patients with in-transit metastases (30–37). Overall, treatment with these agents has mostly been abandoned in more recent years in favor of imiquimod or other classes of immunomodulators with better response rates.
Interleukin-2 (IL-2) is a member of the cytokine family that enhances the growth and proliferation of T cells as well as B cells and lymphokine-activated killer cells (38). It is FDA approved as a systemic agent for metastatic melanoma and has an overall response rate of approximately 10% to 15%, with only a 5% durable response (39). Furthermore, the adverse events have hindered its use. Common side effects include fever, chills, flu-like symptoms, flushing, skin rash, hypotension, and diarrhea. Serious side effects include the capillary leak syndrome, also known as Clarkson’s disease, where intravascular fluid leaks through endothelial cells into the interstitial space (39). This causes hypotension and acute renal failure. When administered intralesionally, the side effect profile is markedly improved (40).
Several large case series reported the efficacy of intralesional IL-2 in stage III and stage IV melanoma. One phase II study in 51 patients with advanced disease reported a complete response rate in 69% of patients after treatment with triweekly intralesional IL-2 (up to 16 million units per session) (41). The response of injected lesions was greater in patients with stage III disease compared with stage IV, and there was no response of untreated lesions (41). Another series of 39 patients treated with biweekly IL-2 for 4 to 7 weeks (mean dose 10.4 million units per session) demonstrated a complete response rate of 51% and partial response of 31% (42). At 5 years, 77% of patients with a complete response remained disease free (42).
The combination of IL-2 with the monoclonal antibody fragment L19 was used to engineer an immunocytokine, L19-IL-2, that may specifically target cancer cells by recognizing markers of tumor angiogenesis (43). A phase II trial of intralesional L19-IL2 and L19-TNF (has synergistic effects with IL-2) in 20 patients with stage IIIC and IV (M1a) metastatic melanoma who were not surgical candidates revealed a complete response in 1 patient (5%), partial response in 10 patients (50%), stable disease in 5 patients (25%), and progressive disease in 4 patients (20%) by week 12 (43). Of the 13 noninjected lesions, a complete response was noted in 7 (53.8 %), including 4 cutaneous lesions and 3 lymph nodes, indicating a systemic anticancer effect (43).
The addition of topical imiquimod to intralesional IL-2 has also been used to treat advanced melanoma. One series of 13 patients with 182 cutaneous lesions of metastatic melanoma showed a 50.5% complete response of intradermal lesions and 40.7% response of subcutaneous lesions (24). These patients were first treated with topical imiquimod for 4 weeks, then intralesional IL-2 three times weekly (mean dose of 3.6 million units per session). In studies that used higher concentrations of intralesional IL-2 (up to 22 million units per session), there were higher response rates (25,40,44). One series demonstrated a 100% response rate when 64 cutaneous and subcutaneous metastatic lesions were treated with high-dose intralesional IL-2 and imiquimod (44). A recent retrospective series of 11 patients treated with combination intralesional IL-2, topical imiquimod, and topical retinoid cream found that 100% of patients achieved a complete local response within 1 to 3 months of treatment (25). Figure 13.2 A to C illustrates a patient from this series that we treated in our practice who developed an exuberant inflammatory response within 2 weeks of therapy, and subsequent resolution of in-transit metastases 2 months later (25,45). The results of such combination regimens are promising and prospective randomized trials are needed to evaluate whether there is a survival benefit.
The overall toxicity profile of intralesional IL-2 is mild compared with the severe adverse events of capillary leak syndrome associated with systemic administration. The most common adverse events with intralesional IL-2 are local injection site reactions (sometimes with intense erythema and ulceration) as well as fever, chills, and flu-like symptoms (25,40–45). The flu-like symptoms may be alleviated by pretreatment with antipyretics. Prophylactic oral and topical antibiotics may be used to prevent bacterial superinfection of ulcerated tumors.
Talimogene laherparepvec (T-VEC) is the first FDA-approved intralesional therapy for advanced, unresectable melanoma. It is an immune-enhanced, oncolytic herpes simplex virus type 1 (HSV-1) genetically engineered to express granulocyte-macrophage colony stimulating factor (GM-CSF), with deletion of neurovirulence factors ICP34.5 and ICP 34 (promoting viral replication in tumor cells) (46). The mechanism of action includes direct tumor cell destruction and promotion of tumor-specific immunity by the effect of GM-CSF on antigen-presenting cells (46).
Source: From Ref. (45). Leventhal JS, Odell I, Imaeda S, et al. Treatment of melanoma in-transit metastases with combination intralesional interleukin-2, topical imiquimod, and tretinoin 0.1% cream. JAAD Case Rep. 2016;2:114–116. With permission.
After a phase II trial of 50 patients with refractory stage III or stage IV disease demonstrated a 26% response rate to T-VEC, including injected as well as noninjected distant metastases, a phase III randomized-controlled study (OPTiM trial) was performed (47