Discussion:
Mucosal Melanoma of the head and neck represent a relatively small pool of malignancies. Not until 2018 was there a work by a team of surgeons, medical oncologists, clinical oncologists, radiologists, pathologists, nurses, as well as patients and carer representatives to form clear guideline on how to manage mucosal melanoma of the head and neck, with a clear pathway diagram outlining steps of referral, assessment and staging, diagnosis, management, and treatment [6].
This paper explores the literature for available studies looking mucosal melanoma of the head and neck and the different treatment modalities available. We looked to find treatment modalities consisting of immunotherapy, with or without other treatment modalities. We looked to compare these to treatment options not involving immunotherapy. The results showed a clear improvement in survival outcomes when immunotherapy was used, compared to survival outcomes without immunotherapy, at all yearly intervals studied. It is pertinent to point out, however, that all studies included a small number of patients, and in many cases, did not clearly define their own inclusion criteria. This could be down to the fact that presentation of disease is variable, both in terms of site and duration.
None of the studies reviewed mentioned randomization of patients, which would have eliminated bias and thus decreased likely discrepancies in treatment received, such as addition of immunotherapy/radiotherapy/chemotherapy to those with poorer prognosis as opposed to surgery alone in those with better prognosis.
There was no report of quality of life in different interventions and therefore no subjective feedback on results from intervention.
Adjuvant immunotherapy with anti-PD-1 agents following complete resection of high-risk (Stage III/IV) melanoma, regardless of subtype, is now standard-of-care (NICE Technology Appraisal Guidance TA553 and TA558) [6].
Immune therapy with checkpoint inhibitors has revolutionized management of melanoma. Ipilimumab, nivolumab, and pembrolizumab are all immune checkpoint inhibitors to treat metastatic melanoma. They work by activating the immune system to treat melanoma .
Ipilimumab targets cytotoxic T-lymphocyte antigen 4 (CTLA-4). By doing so, it down regulates receptors on activated T-cells, whose function is to inhibit T-cell activation. By down-regulating CTLA-4, it allows for expansion of naturally developed melanoma-specific cytotoxic T-cells. It resulted in 11% objective response rate and 24% two-year overall survival.7 The 10-year overall survival of ipilimumab is approximately 22% in a pooled analysis of overall survival data from multiple studies[7].
Nivolumab and pembrolizumab, on the other hand, act by inhibiting programmed cell death ligand 1 (PDL-1). PDL-1 acts to inhibit T-cell proliferation allowing cancer cells to evade immune surveillance[7]. However, the expression of PDL-1 in mucosal melanomas is not well understood. One study, by using immunohistochemical staining in 23 tumor samples from patients with primary mucosal melanoma, found an expression in only 13% (3/23) of mucosal melanomas [8]. Treatment outcomes with these modalities showed mixed results. One paper, which studied the outcomes in both mucosal and acral melanoma treatment with PDL-1 inhibitors, showed an 11.5% response rate to treatment[9]. D’angelo et. al. looked at the efficacy and safety of nivolumab alone or in combination with ipilimumab in patients with mucosal melanoma. Among patients who received nivolumab, median progression-free survival was 3.0 months, with objective response rates of 23.3%. In patients treated with nivolumab in combination with ipilimumab, median progression-free survival was 5.9 months, with objective response rates of 37.1% [10].
Wang Et al reviewed the effect of Interferon-α-2b as an adjuvant therapy and its effect on prolongation of life in patients with previously resected oral mucosal melanoma [11]. Relapse-free survival was significantly prolonged in patients who received postoperative immunotherapy, but there was no significant difference in the overall survival between the those who received immunotherapy versus those who didn’t. [11].
Frakes et. al reviewed a single-center case series of 38 patients, of which 6 (16% of patients) received adjuvant immunotherapy. The study concluded that immunotherapy was not associated with improvements in local control, progression-free or overall survival[12].
The above mentioned papers were in contrast to Kanetaka et al, who looked at the effect of using lymphokine-activated killer (LAK) cell transfer therapy in mucosal melanoma of the head and neck. The sample size included 13 patients over 18 years, with 7 receiving immunotherapy. However, there was no clear explanation if these patients also received chemotherapy. The outcome was that in 7 cases receiving adjunctive LAK cell therapy, the 5-year cause-specific survival rate was 66%, while that in 6 cases without adjunctive LAK therapy was 33%. Although a statistical significance was not recognized, LAK therapy is suggested to improve prognosis of mucosal melanoma of the head and neck[13].
Long et al conducted a double blind, placebo-controlled trial, randomizing 870 patients with completely resected stage III melanoma with BRAF mutation to either BRAF targeted immunotherapy or placebo tables for 12 months. The rates of distant metastasis-free survival and freedom from relapse were higher than in placebo group, with a 53% reduction in relapse or death [14].
In one case report written by Studentova et. al. following disease progression after surgical resections, the patient was treated with ipilimumab monotherapy that was initially followed by disease progression, but subsequently by disappearance of the primary tumor and overall partial response of the disease elsewhere 8 months later. However, the effect lasted only for another 8 months and disease progression occurred followed by death 3 months later[15].
A systematic review conducted by Jarrom et. al.[17] looked at treatment of mucosal melanoma of the upper airway tract. 11 studies were selected looking at surgery and radiotherapy only, with no chemotherapy or biological treatment included. It is noteworthy that since then, more trials have been conducted of which biologics including immunotherapy have been utilized and studied as potential treatment modalities for improving outcomes.