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.