TREATMENT PARADIGMS FOR SNMM
The preferred method of treatment for SNMM is surgery, followed by radiation therapy. However, its patchy and multicentric pattern of growth makes complete surgical resection challenging and often impossible. Thus, other treatment interventions, such as systemic therapies, are required. The rarity of SNMM, together with its high metastatic potential, makes it hard to find efficient systemic therapies to combat this form of melanoma.
Surgical resection with negative margins is the primary treatment modality for SNMM. Surgery can be performed using an open or endoscopic approach. Proponents of endoscopic resection claim it has lower complication rates, though the tumor is resected in a piecemeal manner and not en bloc. Several studies have examined the effect of the surgical approach on patient outcomes.3,37,38 Surgery, whether open or endoscopic, has been shown not to affect overall survival. Whereas post-surgical morbidity appears comparable following endoscopic resection and open resections,37,38 quality of life has been shown to be better after endoscopic resection,39–41 Although level one evidence has not demonstrated the superiority of endoscopic resection over open approaches, endoscopic surgery currently replaces open surgery in over 80% of SNMM cases.42
Regarding surgical margins, the aim of surgery should be complete resection with clear margins. An analysis of a large database of 1874 patients with SNMM found that complete surgical resection with negative margins significantly improves patient prognosis.3 Several other studies showed associations of positive surgical margins with a higher rate of distant metastases, decreased survival measures, and a significantly higher risk of death compared to patients with negative surgical margins.43–45 Thus, surgeons should consider the complex anatomy of the sinonasal cavity, the proximity of the tumor to vital structures, and the pattern of locally-advanced disease (eg orbital invasion, dural invasion, or brain invasion). It is unclear whether radical surgery, which often comes at the cost of significant cosmetic and functional impairments, is justified. Surgical excision as a single-modality therapy should be reserved for patients with small tumors, localized disease, and negative marigns.46
SNMM does not tend to spread to lymph nodes and throughout nerves.3,46,47 Reported rates of regional lymph node metastasis in SNMM are 8–11%.3,48,49 Patients who present with positive lymph nodes require therapeutic neck dissection. Those with regional spread do not have worse outcomes than those without regional spread.3,48 Due to the low rate of regional spread and the lack of effect on survival, elective neck dissection is not recommended.48
The role of chemotherapy is minor compared to the biological and immunological systemic therapies. For example, dacarbazine-based chemotherapy was previously the preferred option for treating patients with metastatic mucosal melanoma.50 However, the lack of association of chemotherapy alone with improved overall survival eventually led to its discontinuation as the standard of care.51
Currently, chemotherapy is used as an adjuvant systemic therapy in combination with other immunotherapeutic and biological drugs after surgical resection in mucosal melanoma.52 Chemotherapeutic drugs, such as dacarbazine, are being used in conjunction with MEK, PD-1, and CTLA-4 inhibitors (see below), as well as with biochemotherapeutic drugs, like interleukin-2 and interferon alfa-2b.53 Most of these combinatorial treatments have yielded disappointing results, with no significant impact on overall survival. Due to the rarity of mucosal melanoma and the stringency with which the benefit of the treatment is determined, chemotherapy is unlikely to be further developed as a monotherapeutic regimen.54
In a Phase II biochemotherapy (BCT) trial, patients were treated with cisplatin, vinblastine, and dacarbazine (CVD) as monotherapies or in conjunction with interleukin-2 and interferon alfa-2b (BCT).55,56 Though BCT showed a higher response rate than CVD, 19.5% vs 13.8% (P=0.140), patients experienced a toxicity of grade 3 or higher. Despite promising results in phase II trials, overall survival rates did not improve in Phase III trials.57 High-dose interferon, which is often used as an adjuvant therapy, or BCT, consisting of CVD, interleukin-2, and granulocyte colony-stimulating factor, were administered to high-risk patients with melanoma in an intergroup phase III trial (S0008). Among the patients receiving BCT, relapse-free survival, but not overall survival improved.58 Hence, BCT provides an alternate approach to treatment. Its primary advantage is the short duration of the treatment, whereas its main caveat is high toxicity. Comparing adjuvant therapies after the resection of mucosal melanoma, temozolomide-based chemotherapy demonstrated better relapse-free survival than did high-dose interferon. A combination of temozolomide with cisplatin is a superior systemic option and may result in better survival rates.59
Aberrations in the KIT gene are highly prevalent in SNMM. This provides an opportunity for systemic therapy by using selective KIT inhibitors. In a phase II trial, the tyrosine kinase inhibitor, imatinib mesylate, showed significant effects in patients with the K642E KIT gene mutation.26 The use of imatinib resulted in control of the disease by 77%, as well as a 54% tumor response rate against the development of an advanced stage of the disease with c-KIT mutations.60 Another tyrosine kinase inhibitor, dasatanib, showed promising results in clinical trials that investigated the most common L576P KIT gene mutation in mucosal melanomas.61 The selective inhibition of various KIT alterations provides an attractive opportunity for developing adjuvant therapies for mucosal melanoma.
Although it’s not as common in SNMM as in other forms of melanoma, the overexpression of the Ras-MAPK signaling pathway in SNMM is another example in which systemic therapy can be implemented. MEK162 is one such allosteric MEK1 and MEK2 inhibitor that has shown promising results in phase III trials conducted in patients with NRAS mutated malignant melanoma. This drug was also shown to be effective against melanomas with BRAF mutations.62 In phase III trials of BRAF-altered metastatic melanoma, vemurafinib, a BRAF kinase inhibitor, showed greater efficacy and tolerability, and also a 20% increase in the 6-month survival rate, compared to the chemotherapeutic dacarbazine.63,64 The effects of the MEK inhibitor, binimetinib (MEK162), were compared to those of dacarbazine in a randomized phase III trial consisting of 400 patients harboring the NRAS mutation in cutaneous melanoma. The administration of binimetinib, before or after one round of immunotherapy, showed better overall response, progression-free survival, and disease control than dacarbazine.62,65 Similar results were seen in another randomized phase III trial in which binimetinib was used in combination with the BRAF inhibitor encorafenib. Compared to vemurafinib monotherapy, this combination showed greater efficacy and tolerability in patients with malignant melanomas.66
In a randomized phase III trial, the use of the cytotoxic T-lymphocyte-associated antigen 4 blocker (CTLA4), ipilimumab, showed a significant increase in median survival (10.1 months), compared to the administration of the glycoprotein 100 (gp100) peptide vaccine (6.4 months).67 In another phase III study, 502 patients with untreated metastatic melanoma were treated with a 1:1 combination of ipilimumab and dacarbazine, where outcomes were compared to dacarbazine monotherapy. The combination treatment showed a statistically significant increase in overall survival of 11.2 months, compared to 9.1 months obtained from dacarbazine monotherapy.68 Hence, multiple prospective and retrospective studies support the use of ipilimumab against this disease.69
The checkpoint inhibitor nivolumab operates by inhibiting interactions of ligands PD-L1 and PD-L2 with its receptor, programmed death-1 receptor (PD-1), thereby blocking T-cell activation. In a phase III trial of patients with ipilimumab-refractory metastatic melanoma, Nivolumab showed a higher overall survival rate (72.9%) than dacarbazine (42.1%).70 Furthermore, in a randomized phase III trial (CheckMate 037), patients who progressed after ipilimumab monotherapy or the combination of ipilimumab and BRAF inhibitor, reported a higher response to nivolumab compared to standard chemotherapy.71 Nivolumab in combination with ipilimumab showed a higher overall response rate (37%) than nivolumab (23%) or ipilimumab (8%) monotherapies, respectively.72 This indicates that the abovementioned combination therapy is more efficient than the systemic therapies that are currently available for mucosal melanoma patients. In addition to nivolumab, other checkpoint inhibitors, such as pembrolizumab, have shown more improvement in progression-free survival, toxicity, and overall survival than ipilimumab, or the investigator-choice chemotherapy drug in the KEYNOTE trials 006 and 002.73,74 Other anti-PD-L1 antibody monotherapies, such as durvalumab and atezolizumab, have also been tested without much success.75
A multivariate analysis of patients with SNMM showed better survival following immunotherapy among patients with metastatic disease (HR: 0.14, 95% CI: 0.04–0.49), but not among those without metastatic disease. This concurs with the more frequent utilization of systemic therapies for advanced rather than localized disease. In that cohort, chemotherapy remained a nonsignificant predictor of survival.3
Treatment of SNMM is challenging due to the complexity and rarity of the disease, as well as the aggressiveness of tumors. Currently, early detection and surgical excision is considered the primary method of treatment. Recent clinical trials demonstrate the effectiveness of systemic therapies in increasing survival rates, thus encouraging the performance of large-scale clinical trials. Furthermore, poor prognosis should provide the impetus to investigate the role of new systemic neoadjuvant combination therapies in the treatment of mucosal melanoma. Table 1 summarizes the ongoing clinical trials for head and neck mucosal melanoma.
Radiation therapy (RT) can be administered to patients with SNMM as a definitive or adjuvant treatment following surgery. Samstein et al reported a retrospective analysis of 78 patients with localized, non-metastatic SNMM who were surgically treated.76 The rate of negative surgical margins was 38%. Eighty-two percent of the patients received RT, 68% as adjuvant treatment and 32% as definitive treatment, due to gross residual disease. Intensity-modulated RT was administered to 45 patients (70%) with the remainder receiving 3D conformal RT. Five-year local recurrence-free survival was higher among patients who received RT than among those who did not (59% vs 35%). The local recurrence rate was 33% among patients who received adjuvant RT, compared to 71% among those who did not. Importantly, the overall survival and disease-specific survival of the two groups was similar.76
Other studies also showed an association of adjuvant RT with reduced locoregional occurrence, but not with overall survival.3,77 According to a recent publication,78 this may be due to low SNMM recurrence of about 20% during the first five years following the commencement of treatment, alongside a high risk of systemic disease. The latter is evidenced by the occurrence of distant metastases in up to 80% of patients within the same period.
Particle beam therapy has also been used to facilitate the delivery of high doses to the residual tumor while minimizing exposure to the surrounding normal tissues.79–81 The reported results of treatment with carbon ion radiotherapy in head and neck mucosal melanoma were 84% for 5-year local control and 27% for 5-year overall survival with acceptable toxicity.81 In patients treated with proton beam therapy, 3-year and 5-year overall survival were 58% and 51% respectively,79,82 Five-year disease-free survival was 38%.82
The role of RT as a primary treatment modality for SNMM remains unclear.83,84 Data in the literature show mainly retrospective outcomes of patients who had definitive RT for unresectable or advanced tumors. Various analyses revealed that definitive RT does not improve survival or disease control of patients with SNMM.1,44,85
Outcomes and Risk Assessment
The prognosis of patients with SNMM remains poor. The reported 5-year overall survival is in the range of 20–60%, while the mean is 27% (Figure 1). Mean, five-year disease-free survival is about 26% (Figure 1). Advanced age is associated with decreased survival.3,5,49 Tumor characteristics that have been associated with worse survival include T4 disease and distant metastasis.3,5,49,76,86 Disease of nasal origin confers better survival than disease of sinus origin.5,49,76,86
An analysis of 1874 patients with SNMM in the National Cancer Database sought to find correlations between treatment modalities and survival measures.3 Surgical resection with negative margins was shown to improve survival (HR: 0.44; 95% CI: 0.30–0.65). This concurs with previous studies.5 Although its effect on survival is yet to be fully realized, immunotherapy was shown to improve the survival rate in the subset of patients with SNMM and distant metastases (HR: 0.14; 95% CI: 0.04–0.49). Surgical treatment, radiotherapy, and chemotherapy were not found to be significant predictors of survival.3 A retrospective study of 198 patients with SNMM, conducted by Amit et al, revealed a recurrence rate of 48%. The most common cause of treatment failure was distant metastasis in 69 (35%), followed by local [36 (18%)] and regional [22 (11%)] recurrence.86 The most common sites for distant metastases were the lungs (20%), followed by the liver (13%), bones (8%), and the brain (5%). Factors with adverse prognostic effects were tumor thickness >4 mm for disease-free survival, positive margins for local recurrence, and bone invasion for distant metastases.86
Similarly, Samstein el al76 reported 66% distant failure, 23% local failure, and 13% regional lymph node recurrence. A subset of patients (n=30) underwent diagnostic genomic testing for mutations of the KIT, BRAF, NRAS, and GNAQ genes. Overall, 30% of them had at least one mutation. Analysis of outcomes in these patients did not reveal a significant prognostication between the presence of mutations and patient outcomes.76
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