The treatment of CMOBC remains difficult and, unfortunately, treatment options do usually not represent long-term solutions. Hence, in this palliative setting, there is a medical need for patient-friendly, not pain-full, skin-directed treatments with a good local tolerance.
This case demonstrated the possibility of treating superficial CMOBC with OFAMTX5% in a painless manner, whilst continuing chemotherapy. OFAMTX5% could be considered as alternative skin-directed therapy such as miltefosine, imiquimod, 5-FU and photodynamic therapy. The principal skin-directed options are discussed hereunder, excluding electrochemotherapy and radiotherapy.
Miltefosine 6% solution is a topical cytostatic agent. Miltefosine interacts with lipids, inhibits cytochrome c-oxidase and leads to an apoptosis-like cell death. Miltefosine was applied to the skin using 2 drops/10 cm2 for often pretreated CMOBC in 25 patients for a median of 14 weeks (range 2-164). Grade 1 and 3 cutaneous toxicities were noted 28% and 16% of the patients, respectively, the latter requiring dose adjustments. A response was observed in 36% of the patients with 1 complete, 2 partial and 6 minor responses. Stable disease was observed in 44% of the patients and progressive disease in 20%. Superficial lesions or lesion less than 2 cm in diameter were the most likely to respond (12).
Later, a double-blind, placebo-controlled, multicenter phase III study evaluated in a cohort of 52 patients with CMOBC with superficial or flat skin lesions with < or = 1 cm of estimated depth, the efficacy and tolerance of 6% miltefosine solution (2 drops/10 cm2), once daily during the first week and twice daily until treatment failure. The time to treatment failure was significantly superior for miltefosine compared to placebo 56 days versus 21 days, respectively. Cutaneous reactions were more frequent in the miltefosine group, although, when present, were well tolerated and only occasionally required treatment interruption (13).
Imiquimod induces endogenous production of interferon mediated by the TLR7 pathway. Imiquimod is a recognized treatment for actinic keratosis and superficial basal cell carcinoma, and used off-label for in situ melanoma and EMPD. Imiquimod 5% cream in combination with cryotherapy was administered in one patient with CMOBC, 3–5 per week, every 3 weeks with initial shrinking of the lesions (8).
A prospective study evaluated in 10 patients with CMOBC the local tumor response rate using topical imiquimod, applied 5 d/week for 8 weeks. Grade 1 to 2 transient local and systemic side effects were observed. A partial response was noted in 20%. Histology revealed tumor regression revealed by changes in the tumor lymphocytic infiltrate and locally produced cytokines (5).
Another paper presented the case of a 26 years-old woman with CMOBC who received topical imiquimod 3x/week for over 4 months, whilst continuing systemic chemotherapy, experiencing a reduction of the lesion thickness, following by a size reduction with no reported adverse effects (3).
A single arm phase 2 clinical study treated 15 patients with CMBOC with 4 days treatment courses for 12 weeks of imiquimod cream 5% while continuing paclitaxel treatment 100 mg/m2. Combination therapy was associated with low-grade toxic effects. Of 358 adverse events 330 (92%) were grades 1 and 2. Five (36%) patients achieved a complete response and another 5 (36%) were partial responders for an overall response rate of 72% (10/14). The response duration was limited. Pretreatment levels of programmed death-1 (PD-1) + peripheral blood T cells (PD-1 + CD4 + and PD-1 + CD8 + and monocytic myeloid derived suppressor cells greater than controls were predictive of suboptimal clinical responses (6).
Using transcriptomic profiling it could be demonstrated that responsiveness to imiquimod therapy for CMOBC with a durable clinical response depended on a permissive microenvironment, substantiated by the upregulation of transcripts encoding for molecules involved in leukocyte adhesion and migration, cytotoxic functions, and antigen presentation. In responding patients, Imiquimod triggered a strong T-helper-1 (Th-1)/cytotoxic immune response, ultimately mediating tumor destruction (7).
5-fluorouracil belongs to the class of antimetabolites and functions like other analogues of pyrimidin. 5-FU 5% cream 2x/d in combination with cryotherapy was used for 4 months with good but transient clinical responses and acceptable local adverse reactions in 2 patients with CMOBC (8).
Photodynamic therapy (PDT), either using topically or intravenously administered photosensitizers, has also been used for CMOBC. In a series of 37 patients with CMOBC, intravenous photofrin II PDT was performed, with 5 complete responses, 13 partial responses and 19 non-responders. The extension and the size of the lesions were the most important predictive parameters for successful responses (9). Topical meso-tetra-porphon (TPPS4)-PDT used in 9 patients with CMOBC revealed 3 complete, 4 partial and 2 non-responders (10). Two elderly patients with CMOBC revealed partial responses after 2 weekly methylaminolevulinate (MAL)-PDT sessions. At 4 weeks, histology showed a clearance of tumor infiltration of the dermis and superficial hypodermis. Unfortunately, persistent tumor nests were still observed in the deep hypodermis (11).
In general, skin-directed therapies for CMOBC, including OFAMTX, could be helpful in superficial lesions regardless of the size. Combination with systemic therapy probably increases the efficacy of skin-directed therapies. Combining skin-directed therapies with different action mechanisms, ie immunostimulatory and antimetabolic, probably further increases effectiveness.
In conclusion, OFAMTX5% was an effective and well-tolerated treatment for superficial CMOBC. More cases will have to be treated in order to determine optimal treatment regimens and, in fine, its place in the armamentarium against CMOBC.