Pulsed Dye Laser Therapy
Another approach for the treatment of intradermal in-transit melanoma metastases is the use of pulsed dye laser therapy (PDL) alone or in conjunction with topical imiquimod(Drug information on imiquimod) (Aldara). The rationale for the use of PDL is that it photocoagulates tumor-associated vasculature and thus induces an inflammatory response in addition to direct tumor photothermolysis. The PDL laser settings used have generally been a 9- to 15-J/cm2 fluence, a 3- to 40-millisecond pulse duration, and a 7-mm spot size.[43-45] Imiquimod, a toll-like receptor agonist, is often used as an adjunct in order to augment the local inflammatory response produced with PDL treatment, potentially creating a systemic antitumor immunity that may induce responses at other untreated sites of disease. Naylor et al reported a complete response in one patient who had disease involving the skin, lung, and regional lymph nodes within 7 months of completing PDL therapy to the in-transit metastasis only.[44] The unique features of PDL that make it attractive include its ease of delivery and tolerability, and its minimal toxicity. Although the results have been mixed, overall patients have tolerated treatment well, with the main side effects being localized pain and swelling, and with most patients reporting an overall improvement in quality of life.[43-45] PDL also has the ability to treat small (< 3 cm) metastases that are inaccessible to ILP (ie, located on the head/neck or trunk).[46] Because of its limited depth of penetration, this technique is only appropriate for superficial intradermal lesions (Figure 3).
Radiotherapy
Dramatic Response to Pulsed Dye Laser (PDL) Treatment
Melanoma has long been considered a radioresistant tumor; however, more contemporary data suggest that the radiosensitivity of melanoma is more heterogeneous.[47,48] External beam radiation is rarely used as primary treatment for locoregional recurrent melanoma; however, it can be useful for unresectable in-transit melanoma. A single institutional review of 120 patients with advanced melanoma, including 33 patients with in-transit disease, reported a 3-month response rate in stage III patients of 77%, including 44% with a complete response. Complete response was closely associated with improved survival. The median survival for patients specifically with in-transit melanoma was 19 months, and the 1- and 5-year overall survivals were 69% and 32%, respectively.[49] Radiation was well tolerated, and 95% of patients were able to complete treatment; patients who received a radiation dose of less than 40 Gy had a significantly worse overall survival than those receiving 40 to 50 Gy. Radiation doses of greater than 50 Gy did not seem to improve overall survival.[49] As in other tumors, radiotherapy is often most effective in treating microscopic residual disease, as opposed to gross disease, serving as an adjuvant therapy that can be utilized following local R0 resections of in-transit metastasis confined to a limited field. Because it obliterates the lymphatic network, radiation therapy is also associated with lymphedema, and circumferential treatment would thus be a relative contraindication. External beam radiation has also been demonstrated to be very effective in treating in-transit melanoma of the head and neck, and given the lack of other effective treatment modalities and the cosmetic concerns about this location, we routinely utilize primary or adjuvant radiation in patients with in-transit melanoma of the head and neck.[49]
Therapeutic Agents
Mentioned in This Article
ADH-1 (Exherin)
Bacille Calmette Guérin
Bevacizumab(Drug information on bevacizumab) (Avastin)
Bleomycin(Drug information on bleomycin)
Carboplatin(Drug information on carboplatin)
Cisplatin
Dacarbazine(Drug information on dacarbazine)
Granulocyte macrophage colony– stimulating factor (GM-CSF)
Imiquimod (Aldara)
Interferon-α
Interleukin-2 (IL-2)
Ipilimumab (Yervoy)
Melphalan(Drug information on melphalan)
Oncolytic herpes simplex virus type 1 encoding GM-CSF (OncoVEXGM-CSF)
Paclitaxel(Drug information on paclitaxel)
Sorafenib(Drug information on sorafenib) (Nexavar)
Temozolomide(Drug information on temozolomide) (Temodar)
Tumor necrosis factor (TNF)-α
Vemurafenib (Zelboraf))
Brand names are listed in parentheses only if a drug is not available generically and is marketed as no more than two trademarked or registered products. More familiar alternative generic designations may also be included parenthetically.
Systemic Therapy
As noted, in-transit disease represents advanced stage III disease that is potentially curable but often unresectable. In a recent retrospective review, 56% of patients with in-transit disease as the sole site of first recurrence subsequently developed distant disease. Large in-transit metastasis with a diameter ≥ 2 cm was the only independent predictor of distant metastasis (odds ratio [OR], 9.69).[2] For patients who fail to respond to locoregional therapy or who develop synchronous or metachronous distant metastasis, systemic therapy is indicated.
Until recently, dacarbazine (DTIC) and IL-2 were the only FDA-approved systemic agents for metastatic melanoma. High-dose IL-2 has demonstrated only a 16% response rate, and the drug’s approval was based on the rare but potentially curative 6% durable complete response rate.[50] Nonvisceral disease is consistently associated with a higher rate of complete response to high-dose IL-2—up to 50% in the setting of M1a disease in some studies—and this therapy therefore may be considered for those with in-transit disease.[50-52] The obvious limitation remains its significant toxicity profile and low overall complete response rate.
Recently there has been dramatic improvement in the systemic treatment of patients with disseminated melanoma. Ipilimumab (Yervoy), a fully humanized IgG1 monoclonal antibody against cytotoxic T lymphocyte–associated antigen 4 (CTLA-4), was recently approved by the FDA as immunotherapy for the treatment of metastatic melanoma. Ipilimumab in combination with DTIC significantly improved duration of response and overall survival compared with DTIC alone in a large randomized controlled trial.[53] However, this study consisted primarily of patients with stage IV disease, with only 2% to 3% of patients having unresectable stage III disease. Ipilimumab following HILP with melphalan is currently being investigated for patients with in-transit melanoma, and the results of this study may lead to further utilization of this agent for locoregionally advanced melanoma (protocol ID 10-101, NCT01323517).
BRAF is a serine threonine protein kinase that is a component of the mitogen-activated kinase pathway. About half of human melanomas have been shown to have an activating mutation in BRAF due to a substitution of glutamic acid for valine at amino acid 600 (V600E).[54,55] Sorafenib (Nexavar) is a nonspecific, multikinase inhibitor that has been demonstrated to enhance the cytotoxic effects of melphalan in melanoma cell lines as well as in an animal model [56]; unfortunately, in the clinical setting it did not add any benefit to carboplatin and paclitaxel in the treatment of stage III and IV melanoma.[57] Vemurafenib (PLX4032; Zelboraf) is a potent inhibitor of mutated BRAF that was recently shown to improve overall survival in patients with stage IIIC or stage IV melanoma that tested positive for the BRAF V600E mutation [58]. Subsequently vemurafenib was approved by the FDA for unresectable melanoma. Currently there are no studies evaluating vemurafenib specifically in locoregionally advanced melanoma.
There is also great interest in the inhibition of vascular endothelial growth factor (VEGF) in melanoma. Bevacizumab (Avastin) is a monoclonal antibody against VEGF that is used for the treatment of metastatic colorectal, brain, non–small-cell lung, and breast cancers. In a phase II trial of carboplatin and paclitaxel with bevacizumab in stage IV melanoma, there was a median progression-free survival of 6 months and an overall survival of 12 months.[59] A phase III trial of carboplatin and paclitaxel with or without bevacizumab in patients with stage IV melanoma demonstrated a clinically but not statistically significant difference in progression-free survival (5.6 months vs 4.2 months) and in overall survival (12.3 months vs 9.2 months).[60] However, only patients with stage IV melanoma were included in these trials, not those with in-transit disease. Bevacizumab in combination with melphalan has demonstrated a marked synergistic antitumor effect in a xenograft model, suggesting VEGF inhibition may alter vascular permeability, leading to increased melphalan delivery during HILP for in-transit melanoma.[61]
Electrochemotherapy
Electrochemotherapy (ECT) consists of chemotherapy with subsequent application of electrical fields to increase tumor cell membrane permeability. When applied to in-transit and cutaneous metastases, electroporation has the potential to enhance penetration of intralesional and intravenous chemotherapy. Cisplatin(Drug information on cisplatin) and bleomycin have demonstrated high efficacy in this setting. Although both agents are given in subtherapeutic doses, the electroporation enhances cytotoxicity 10- to 700-fold.[62] Objective response rates of up to 96% have been reported, with 50% to 78% complete responses.[63,64] Unfortunately, ECT fails to induce a regional and systemic immunization to melanoma antigens, and most patients experience progression.[63] Although this approach is promising, we do not currently offer ECT, and therefore it is not included in our algorithm.
Conclusion
Unfortunately, despite aggressive treatment, relapse is the rule rather than the exception in patients with in-transit melanoma. Survival is mainly dictated by the biological behavior of the disease, and most patients can expect to experience multiple treatment regimens. In-transit melanoma is not a single disease entity; instead, it represents diverse and complex patterns of failure. For each treatment, there is a select group of patients who will have a complete response and long-term survival. Future studies will need to identify which patient and tumor characteristics respond to each approach. Since these tumors are easily accessible, they offer the unique opportunity for pre- and post-treatment tissue analysis to identify genetic signatures. A better understanding of chemotherapy resistance pathways, biologic targets, gene expression profiles, and markers predictive of response to each therapy will allow rational preoperative determination of individualized treatment as opposed to the broad generalized clinically based guidelines we have outlined.
Financial Disclosure: The authors have no significant financial interest or other relationship with the manufacturers of any products or providers of any service mentioned in this article.
