Combination of Postoperative Adjuvant Chemoradiotherapy and Immune Checkpoint Inhibitors Significantly Prolongs Recurrence-Free Survival in Sinonasal Mucosal Melanoma

Abstract

Importance

The currently recommended postoperative adjuvant treatment for sinonasal mucosal melanoma (SNMM) (chemotherapy, optionally accompanied by local radiotherapy) has limited efficacy.

Objective

We aimed to provide a potentially optimal adjuvant therapeutic strategy for patients with SNMM.

Design

Retrospective cohort study.

Setting

Our hospital’s cancer center.

Participants

Seventy-nine patients with stage III/IV SNMM who underwent complete resection and received adjuvant radiotherapy between April 2012 and October 2022 were included in the study.

Interventions

Patients were categorized into 2 groups based on different adjuvant medical regimens: a temozolomide/dacarbazine-based chemotherapy group (n = 44) and a temozolomide/dacarbazine chemotherapy plus PD-1 inhibitor group (n = 35).

Main outcome measures

These included recurrence-free survival (RFS), distant metastasis-free survival (DMFS), failure patterns, and overall survival (OS).

Results

The median follow-up duration was 56.8 (8.85-104.75) months in the chemotherapy group and 27.7 (14.53-40.87) months in the chemotherapy plus PD-1 inhibitor group, respectively. Relative to adjuvant chemoradiotherapy, the combination of additional PD-1 inhibitor significantly prolonged RFS (mRFS: 10.0 months vs 18.9 months; HR, 0.43; 95% CI, 0.25-0.75; P = .002), DMFS (mDMFS: 11.2 months vs 18.9 months; HR, 0.48; 95% CI, 0.27-0.84; P = .009), and OS (29.1 months vs NA; HR, 0.36; 95% CI, 0.17-0.77; P = .006) in patients with SNMM. Within a 2-year timeframe, patients in the chemotherapy plus PD-1 inhibitor group exhibited a lower regional recurrence rate than those in the chemotherapy group (0.0% vs 18.8%, P < .001). The 2-year OS rates in the adjuvant chemotherapy group and the chemotherapy combined with PD-1 inhibitor group were 54.5% versus 75.7%, respectively, while the corresponding 4-year OS rates were 20.9% and 62.4%.

Conclusions and relevance

Surgery followed by adjuvant chemoradiotherapy and prompt initiation of PD-1 inhibitor therapy may improve local disease control in patients with SNMM.

Graphical Abstract

Keywords

immune checkpoint inhibitors adjuvant treatment mucosal melanoma

Introduction

Mucosal melanoma (MM) is a rare malignancy and is characterized by a high degree of aggressiveness and a poor prognosis.¹ Over half of MMs are head and neck mucosal melanomas (HNMM), with >60% originating in the nasal cavity and sinuses.^2
-4 The 5-year overall survival (OS) rate of patients with sinonasal mucosal melanoma (SNMM) is <40%, with an approximate local recurrence rate of 50% and frequent metastasis.^5,6 For these patients, radiotherapy and/or chemotherapy have been used as postoperative adjuvant treatment options.^7
-9 Postoperative adjuvant radiotherapy is reported to effectively control locoregional recurrence and improve local disease-free survival; however, few studies support its impact on OS.^10
-14 Meanwhile, a temozolomide-based adjuvant chemotherapy regimen has been shown to significantly prolong recurrence-free survival (RFS), although its impact on OS remains controversial.^15,16 Given the limitation of the efficacy of traditional adjuvant therapy, immune checkpoint inhibitors (ICIs) have emerged as potentially attractive agents for the treatment of SNMM due to their efficacy in adjuvant therapy for all-site MM.^17
-20 To date, the available evidence for administering adjuvant ICIs to patients with SNMM is mainly based on retrospective analyses^21,22 and small subgroups in clinical trials.²³ The relatively meaningful evidence available stems from 2 systematic reviews encompassing large sample sizes of patients with SNMM, which consistently demonstrated a stronger trend toward clinical benefits with adjuvant ICI.^24,25 The above research background necessitates further exploration of the clinical efficacy of combined ICIs in the context of postoperative adjuvant chemoradiotherapy.

We previously reported the efficacy and safety of postoperative radiotherapy in HNMM through a single-arm phase II study, which particularly focused on the control of recurrence and metastasis.²⁶ HNMM encompasses SNMM and oral MM; however, the prognosis differs between the 2 types. This paper, therefore, aimed to investigate the efficacy of patients with SNMM who received postoperative adjuvant therapy at our cancer center. To address this clinically relevant concern, the efficacy of patients who underwent postoperative chemoradiotherapy combined with a PD-1 inhibitor was evaluated. To date, comprehensive studies summarizing the impact of adjuvant chemoradiotherapy on recurrence, metastasis, and survival outcomes in patients with SNMM compared to those of the combination of chemoradiotherapy with ICI are lacking. The purpose of this study was to provide evidence to facilitate clinical decision-making in determining the optimal adjuvant therapy for patients with SNMM.

Methods

Patients

This retrospective single-center real-world analysis was conducted in accordance with the principles of the Declaration of Helsinki. The data were collected from patients with stage III/IV SNMM (HNMM grading, Cancer Staging Manual, 7th edition, AJCC) at our institution’s cancer center between April 2012 and October 2022. Pathological diagnoses were all confirmed by experienced pathologists. All enrolled 79 patients underwent radical resection, and post-surgical imaging confirmed tumor-free status and was followed by adjuvant radiotherapy. Based on different postoperative adjuvant systemic treatments, the patients with SNMM were categorized into 2 groups: a temozolomide/dacarbazine-based chemotherapy group and a temozolomide/dacarbazine chemotherapy combined with PD-1 inhibitor group. Demographic, clinical, and survival data of the enrolled patients were extracted from medical records.

Adjuvant Treatment

Intensity-modulated radiotherapy was administered to each patient within 4 to 6 weeks after surgery. The radiotherapy plan was developed and administered by the radiotherapy radiologist in our multidisciplinary team. During radiotherapy, temozolomide was administered orally at 75 mg/m²/day until radiotherapy completion. The administration of temozolomide therapy was continued, allowing for a rest period of approximately 4 weeks subsequent to the completion of radiotherapy. Patients in the chemotherapy group were administered one of three treatment options: temozolomide monotherapy, dacarbazine monotherapy, or temozolomide plus cisplatin. Patients in the chemotherapy plus PD-1 inhibitor group had 2 options available: either temozolomide or dacarbazine combined with a PD-1 inhibitor. The dose-dense temozolomide regimen was administered in a 28-day cycle at 75 mg/m² from day 1 to day 21, followed by a discontinuation period of 7 days. Dacarbazine, whose efficacy is comparable to that of temozolomide, was administered intravenously once daily for 5 days at 200 mg/m². Five patients with early cancer diagnosis in the chemotherapy group were administered a combination of temozolomide and cisplatin, where cisplatin was administered at 75 mg/m² on day 1, and temozolomide was administered at 75 mg/m²/day from day 1 to day 5, following a 21-day cycle. The PD-1 inhibitors administered to the patients included in this study were pembrolizumab and toripalimab. The doses of pembrolizumab and toripalimab administered were 200 and 240 mg, respectively, with a frequency of once every 3 weeks. These PD-1 inhibitors were typically administered as intended until disease recurrence, the onset of intolerable adverse events (AEs), or completion of planned cycles.

Efficacy Evaluation

The objectives of the present study were to assess the RFS, distant metastasis-free survival (DMFS), and OS and determine the first recurrence pattern and potential prognostic factors. RFS was defined as the time from adjuvant therapy commencement until the first recurrence or death from any cause, while DMFS was defined as the time from adjuvant therapy commencement until the first occurrence of distant metastases or death from any cause. OS was calculated from the first day of adjuvant treatment until the day of death from any cause.

The pre-treatment assessment included nasopharyngeal and neck magnetic resonance imaging, as well as computed tomography scans of the chest and upper abdomen, conducted post-surgery. These examinations were performed every 3 months throughout the treatment period as monitoring for recurrence. Therapeutic efficacy was assessed using the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. Adverse effects of treatment were assessed according to the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAEs) version 4.0.

Statistical Analysis

Statistical analyses were conducted using SPSS (version 23.0; IBM Corporation, Chicago, Illinois, USA), GraphPad Prism 9, and R (version 4.3.1; R Foundation, Vienna, Austria). Categorical data are presented as frequencies or percentages, while continuous data are presented as the median (range) for normally distributed data. Adjusted χ², χ², or Fisher’s exact tests were used to compare baseline data between the 2 groups. The probability of RFS and DMFS was estimated using the Kaplan–Meier method, with significance evaluated using the log-rank test. A Cox proportional hazards model was used to calculate the hazard ratio (HR) for each time-to-event analysis for the chemotherapy plus PD-1 inhibitor group relative to the chemotherapy group, along with 95% confidence intervals (CI). All statistical analyses were 2-sided, and significance was determined at P < .05.

Results

Screening Procedure and Patient Characteristics

Our center admitted a total of 174 patients diagnosed with SNMM between April 2012 and October 2022. However, 80 patients were excluded due to their inability to undergo radical resection at diagnosis (n = 33) or lack of standard adjuvant care after surgery (n = 47). Patients who did not undergo efficacy evaluation (n = 14) after receiving surgery and adjuvant treatment and those with secondary tumors (n = 1) were also excluded. The final analysis included 79 eligible patients who underwent surgery and adjuvant radiotherapy; they were further categorized into a temozolomide/dacarbazine-based chemotherapy group (n = 44) and a temozolomide/dacarbazine chemotherapy combined with PD-1 inhibitor group (n = 35). A detailed screening flowchart is provided in Figure 1.

Figure 1.

Screening procedure flowchart. TMZ, Temozolomide; DTIC, Dacarbazine; PD-1 inhibitor, programmed death-1 inhibitor.

The baseline clinical characteristics of the enrolled patients are presented in Table 1, with more detailed information provided in Supplemental Table 1. Both males and females accounted for 50.0% in the chemotherapy group, while males accounted for 51.4% in the chemoimmunotherapy group. The median age at baseline was 58 years in the chemotherapy group, while it was 61 in the other group. Based on the HNMM grading, 17 (38.6%) patients had stage III disease, 25 (56.8%) had stage IVA disease, and only 2 (4.6%) had stage IVB disease in the chemotherapy group. In comparison, the chemoimmunotherapy group included 16 (45.7%) patients with stage III disease, 16 (45.7%) with stage IVA disease, and 3 (8.6%) with stage IVB disease. There was one patient with regional lymph node metastasis confirmed by pathology after lymph node dissection in the chemotherapy group, while there were 2 such cases in the chemoimmunotherapy group, suggesting that SNMM has a low incidence of regional lymph node metastasis. Notably, temozolomide plus cisplatin was administered to 5 (11.4%) patients in the chemotherapy group. In contrast, none of the patients (0.0%) in the chemotherapy combined with PD-1 group received that chemotherapy regimen (P > .05). Moreover, all 35 patients in the chemoimmunotherapy group had wild-type BRAF, as did 31 patients who were tested for BRAF mutation in the chemotherapy group. Overall, the baseline clinical features were statistically well-balanced between the 2 treatment groups.

Table 1.

Demographic and Clinical Characteristics of Patients at Baseline.

Characteristic	Chemotherapy (n = 44)	Chemotherapy + PD-1 inhibitor (n = 35)	P-value
Characteristic	N (%)	N (%)	P-value
Gender
Male	22 (50.0)	18 (51.4)	.900
Female	22 (50.0)	17 (48.6)	.900
Age, years
Median (range)	58 (26-75)	61 (43-72)	.721
<65	33 (75.0)	25 (71.4)
≥65	11 (25.0)	10 (28.6)
KPS
100	2 (4.6)	3 (8.6)	.518
90	39 (88.6)	28 (80.0)
80	3 (6.8)	4 (11.4)
Stage (AJCC 7th)
Stage III	17 (38.6)	16 (45.7)	.591
Stage IVA	25 (56.8)	16 (45.7)
Stage IVB	2 (4.6)	3 (8.6)
Primary tumor (T)
T3	18 (40.9)	16 (45.7)	.675
T4a	24 (54.5)	16 (45.7)
T4b	2 (4.6)	3 (8.6)
Nodal metastasis (N)
N1	1 (2.3)	2 (5.7)	.581
N0	43 (97.7)	33 (94.3)	.581
Temozolomide-based chemotherapy regimens
TMZ/DTIC	39 (88.6)	35 (100.0)	.063
TMZ/DTIC + Cisplatin	5 (11.4)	0 (0.0)	.063
LDH (U/L)
≤ULN	32 (72.7)	23 (65.7)	.807
>ULN	1 (2.3)	1 (2.9)
Unknown	11 (25.0)	11 (31.4)
BRAF^V600E/K mutation
Wild-type	31 (70.5)	35 (100.0)	.000
Mutated	0 (0.0)	0 (0.0)
Unknown	13 (29.5)	0 (0.0)
MDM2 amplification
Negative	21 (47.7)	30 (85.7)	.001
Positive	1 (2.3)	0 (0.0)
Unknown	22 (50.0)	5 (14.3)
MGMT promoter methylation status
Negative	12 (27.3)	23 (65.7)	.000
Positive	2 (4.5)	3 (8.6)
Unknown	30 (68.2)	9 (25.7)
NRAS mutation status
Wild-type	16 (36.3)	24 (68.6)	.000
Mutated	5 (11.4)	8 (22.8)
Unknown	23 (52.3)	3 (8.6)
PD-L1 status
Positive	3 (6.8)	2 (5.7)	.904
Negative	5 (11.4)	3 (8.6)
Unknown	36 (81.8)	30 (85.7)
Ki67 (%)
<50%	25 (56.8)	20 (57.2)	.764
≥50%	9 (20.5)	9 (25.7)
Unknown	10 (22.7)	6 (17.1)

Abbreviations: AJCC, American Joint Committee on Cancer; KPS, Karnofsky performance status; LDH, lactate dehydrogenase; MDM2, mouse double minute 2 homolog; MGMT, O⁶-methylguanine methyltransferase; NRAS, neuroblastoma RAS viral oncogene homolog; ULN, upper limit of normal value.

Treatment Status

The median (range) follow-up duration was 56.8 (8.85-104.75) months in the chemotherapy group and 27.7 (14.53-40.87) months in the chemotherapy plus PD-1 inhibitor group. In the chemotherapy plus PD-1 inhibitor group, pembrolizumab and toripalimab were administered to 23/35 (65.7%) and 12/35 (34.3%) patients, respectively. Among patients in the chemotherapy group, 41 (93.2%) were treated with oral temozolomide and 3 (6.8%) with intravenous dacarbazine. In comparison, 23 (65.7%) and 12 (34.3%) patients received oral temozolomide and intravenous dacarbazine, respectively, in the chemotherapy plus PD-1 inhibitor group.

By the end of the follow-up, all 44 (100.0%) patients in the chemotherapy group had discontinued treatment for various reasons, while 34 (97.1%) patients in the chemotherapy combined with PD-1 inhibitor group had ceased treatment, and 1 (2.9%) patient was still undergoing systemic adjuvant immunotherapy. In the chemotherapy group, 22 (50.0%) patients successfully completed planned cycles of adjuvant chemotherapy following completion of concurrent chemotherapy, as intended. In contrast, among the 34 patients in the chemotherapy plus PD-1 inhibitor group who had stopped taking the drug, 27 (27/34, 79.4%) patients completed 4 to 6 cycles of adjuvant chemotherapy. Among them, 16/34 (47.1%) patients also achieved successful completion of 1 year of PD-1 antibody maintenance therapy. In the chemotherapy group, treatment was discontinued by 15 (34.1%) patients due to disease recurrence, whereas in the chemotherapy plus PD-1 inhibitor group, treatment was halted by 13/34 (38.2%) patients due to disease recurrence. Additionally, 1 (2.3%) in the chemotherapy group and 1 (2.9%) patient receiving combination therapy discontinued treatment because of therapy-related AEs. Six (13.6%) individuals in the chemotherapy group terminated their medication use due to factors including the COVID-19 pandemic, personal preference, and financial constraints; 4/34 (11.8%) patients receiving combination therapy did so for similar reasons. Only 1 patient in the chemotherapy combined with PD-1 inhibitor group who had not discontinued the medication is currently undergoing maintenance treatment with PD-1 inhibitors and has not yet experienced disease recurrence.

Recurrence-Free Survival

Figure 2A shows the RFS curves of the 2 adjuvant treatment groups, suggesting that the chemotherapy combined with PD-1 inhibitors regimen tended to more significantly improve the RFS of patients with resected SNMM than the chemotherapy regimen (P = .002). In the chemotherapy group, the mRFS was approximately 10.0 (95% CI, 6.97-15.70) months, whereas it was approximately 18.9 (95% CI, 9.70-NA) months in the chemotherapy plus PD-1 inhibitor group; the HR point estimate for the treatment comparison was 0.43 (95% CI, 0.25-0.75). By the end of follow-up, relapse or death from any cause occurred in 38/44 (86.4%) and 21/35 (60.0%) patients in the chemotherapy and chemotherapy plus PD-1 inhibitor groups, respectively. Additionally, local recurrence and/or distant metastasis was observed in 22/44 (50.0%) and 14/35 (40.0%) patients in the chemotherapy and in chemotherapy plus PD-1 inhibitor groups, respectively, within 1 year of the initiation of treatment. From the first day of treatment to the end of month 18, relapse or death increased to 28 (63.6%) cases in the chemotherapy group and 16 (45.7%) cases in the chemotherapy plus PD-1 inhibitor group. Within a 2-year frame, the total count of endpoint events of RFS had been observed in 34 (77.3%) and 17 (48.6%) patients in the chemotherapy and chemotherapy plus PD-1 inhibitor groups, respectively. Importantly, by the end of the follow-up period, a total of 9 out of the 14 patients in the chemotherapy plus PD-1 inhibitor group who had not experienced recurrence achieved a RFS duration exceeding 2 years.

Figure 2.

(A) Kaplan–Meier curves of recurrence-free survival comparing outcomes of patients with SNMM who received adjuvant chemotherapy alone versus those of patients who received adjuvant chemotherapy in combination with a PD-1 inhibitor. (B) Forest plot comparing recurrence-free survival among patients with mucosal melanoma, categorized by subgroup. SNMM, sinonasal mucosal melanoma.

A subgroup forest plot analysis of RFS showed that the following subgroups were more likely to benefit from chemotherapy combined with PD-1 inhibitor therapy: women, patients younger than 65 years, those with an earlier TNM stage (stage III) at inclusion in the analysis, those with stage T3 disease, those with no lymph-node metastasis at baseline, and those with a lower Ki67 (<50%) (Figure 2B).

Distant Metastasis-Free Survival

The results indicated that the addition of anti-PD-1 antibody to postoperative adjuvant chemoradiotherapy significantly improved the DMFS outcome (mDMFS: 11.2 months vs 18.9 months; HR, 0.48; 95% CI, 0.27-0.84; P = .009) (Figure 3A). Moreover, we conducted a subgroup analysis of DMFS (Figure 3B). A subgroup forest plot analysis of DMFS showed that the following groups were more likely to benefit from chemotherapy combined with PD-1 inhibitor adjuvant therapy: patients younger than 65 years, those with an earlier TNM stage (stage III), those with stage T3 disease, those with no lymph-node metastasis at baseline, and those with a lower Ki67 (<50%).

Figure 3.

(A) Kaplan–Meier curves comparing the distant metastasis-free survival outcomes of patients with sinonasal mucosal melanoma who received adjuvant chemotherapy alone versus those of patients who received adjuvant chemotherapy combined with a PD-1 inhibitor. (B) Forest plot comparing distant metastasis-free survival among patients with mucosal melanoma, categorized by subgroup.

Failure Patterns

Two (4.5%) patients in the chemotherapy group were excluded from the analysis of the first recurrence pattern due to unconfirmed relapse events before death from any cause. Therefore, to mitigate the impact of varying follow-up durations on statistical accuracy, the incidence of first recurrence within a 2-year timeframe was compared between the 2 groups (Figure 4). A total of 32 (72.7%) patients in the chemotherapy group experienced an initial relapse within 2 years of commencing treatment, compared to 17 (48.6%) in the chemotherapy combined with PD-1 inhibitor group. Moreover, among those identified as having relapsed, 3/32 (9.4%) patients in the chemotherapy group exhibited simple regional recurrence, which was significantly higher than in the chemotherapy combined with PD-1 inhibitor group, where no simple regional recurrence (0.0%) was recorded (P < .01). Likewise, 3 (9.4%) patients in the chemotherapy group and no (0.0%) patient in the chemoimmunotherapy group experienced a combination of distant metastasis and nasal regional recurrence (P < .01). Accordingly, there was a lower proportion of simple distant metastasis in patients receiving the chemotherapy regimen (26/32, 81.2%) than in those receiving chemotherapy plus PD-1 inhibitors (17/17, 100.0%) (P < .001). Importantly, these data indicate that the addition of a PD-1 inhibitor to postoperative adjuvant chemoradiotherapy can significantly improve local control in the nasal region in patients with resected SNMM (18.8% vs 0.0%, P < .001).

Figure 4.

Bar chart illustrating the distribution of patients with recurrence within 2 years based on the adjuvant treatment regimens they received and relapse patterns.

To investigate whether there were preferred sites of distant metastasis in patients in different adjuvant treatment groups, we next assessed the initial distant metastasis pattern within a 2-year timeframe (Figure 5). Within a 2-year period of commencing treatment, distant metastasis had occurred in 31/42 (73.8%) patients in the chemotherapy group and in 17/35 (48.6%) patients in the chemoimmunotherapy group. Importantly, relative to adjuvant chemotherapy alone, the addition of anti-PD-1 antibodies significantly reduced the incidence of lung and pleural metastases (67.7% vs 52.9%, P < .05). However, bone metastases were observed in 52.9% (9/17) of patients receiving chemotherapy plus PD-1 inhibitor at the moment of initial distant metastasis, relative to only 25.8% (8/31) in the control group receiving chemotherapy alone (P < .001). Nevertheless, the median time to the occurrence of bone metastasis was later in the chemoimmunotherapy group than in the chemotherapy group (7.7 months vs 5.0 months, P < .01).

Figure 5.

Bar graph illustrating the frequency of metastases at each site at the time of initial distant metastasis within 2 years in patients with mucosal melanoma.

Overall Survival

As at September 2024, 36 (45.6%) patients in the study had died, with 27 (61.4%) in the chemotherapy group and 9 (25.7%) in the chemotherapy plus PD-1 inhibitor group. The results of the OS analyses for the patients with resected SNMM who received the 2 adjuvant treatment regimens are shown in Figure 6. The median OS was longer in the chemotherapy plus PD-1 inhibitor group (not arrived, NA) than in the chemotherapy group (29.1 months; P = .006), and the HR point estimate for the treatment comparison was 0.36 (95% CI, 0.17-0.77). Furthermore, the 2-year and 4-year OS rates for patients in the chemotherapy group were 54.5% and 20.9%. The corresponding data in the chemotherapy plus PD-1 inhibitor group were 75.7% and 62.4%, respectively.

Figure 6.

Kaplan–Meier curves of overall survival comparing outcomes of patients with SNMM who received adjuvant chemotherapy alone versus those of patients who received adjuvant chemotherapy in combination with a PD-1 inhibitor. SNMM, sinonasal mucosal melanoma.

Safety

No unexpected AEs were observed in either treatment group. The incidence rates of radiation-related acute AEs (including common events, such as dermatitis, mucositis, anemia, and leukopenia) during adjuvant radiotherapy were similar between the 2 groups, both exceeding 50%, with most being grade 1 to 2 in severity. Notably, 3 (6.8%) patients in the chemotherapy group experienced grade 3 radiation-related AEs, including one case of grade 3 oral mucositis, one case of radiation-related decreased albumin, and one case of radiation-related pneumonia, which resulted in a temporary interruption of adjuvant therapy. Similarly, 3 (8.6%) grade 3 radiation-related acute AEs were reported in the group receiving chemotherapy combined with a PD-1 inhibitor. The occurrence of grade 3 oral mucositis was observed in 2 cases. The rest one presented as limited mouth opening, multiple oral ulcers, oral leukoplakia, and dysphagia; in addition to immediate cessation of radiotherapy, the patient was provided with symptomatic management by gastrostomy. No grade 3 to 4 late complications associated with radiotherapy were observed in either group.

During systemic adjuvant therapy, 26 (59.1%) patients in the chemotherapy group experienced AEs of any grade. Among these, the most common chemotherapy-related AEs were digestive symptoms (50.0%), hematological toxicity (36.4%), and mouth ulcers (34.1%). In contrast, 22 (62.9%) patients in the chemotherapy combined with PD-1 inhibitor group had AEs of any grade, and the rate of chemotherapy-related AEs was roughly comparable with that in the chemotherapy alone group. Notably, additional immune-related AEs, such as vitiligo, rash, and hypothyroidism, were also reported in the chemotherapy combined with PD-1 inhibitor group. As previously mentioned, the majority of treatment-related AEs experienced by patients were classified as grade 1 to 2; however, one patient in each group discontinued treatment due to grade 3 AEs during systemic adjuvant therapy. In the chemotherapy group, a patient had developed oral mucositis during radiotherapy, which initially improved with symptomatic management. Nevertheless, the condition worsened and persisted during oral administration of temozolomide, ultimately leading to treatment interruption and patient withdrawal. One patient in the chemotherapy plus PD-1 inhibitor group experienced dizziness, vomiting, keratitis, frequent premature ventricular contractions, and a progressive increase in creatinine levels, necessitating discontinuation of immunotherapy. Both patients exhibited shorter RFS and DMFS compared to the median values of their group. Notably, no grade 4 chemotherapy- or immunotherapy-related AEs, nor any treatment-related deaths, were observed in either treatment group.

Discussion

To date, our study represents the first report comparing recurrence, metastasis, and survival outcomes in SNMM between adjuvant chemoradiotherapy and the combination of chemoradiotherapy and ICIs. More significantly, it provides a potentially optimal adjuvant treatment strategy based on the existing recommended adjuvant chemotherapy for SNMM. Surprisingly, in this real-world analysis, the data presented demonstrate that, among included patients with completely resectable SNMM who all received postoperative adjuvant chemoradiotherapy, the addition of PD-1 inhibitors significantly prolonged RFS, DMFS, and OS. Notably, the 2-year local nasal recurrence rate was significantly lower in the chemotherapy combined with PD-1 inhibitor group than in the group receiving only chemotherapy (0.0% vs 18.8%, P < .001).

The utilization of temozolomide-based chemotherapy has long been considered the preferred postoperative adjuvant treatment option for patients with MM, and this is supported by multiple studies conducted in Chinese populations. The findings of phase II and III trials that compared adjuvant temozolomide plus cisplatin chemotherapy to high-dose interferon (HDI) therapy in Chinese patients with resected MM demonstrated the superior efficacy of chemotherapy over HDI.^15,16 Recently, a real-world retrospective cohort study of patients with MM presented at ASCO 2023 revealed that the mRFS and mDMFS were 28.2 and 42.0 months, respectively, in the temozolomide plus cisplatin chemotherapy group, while they were 12.0 and 19.0 months, respectively, in the toripalimab monotherapy group.¹⁹ In contrast, the mRFS of patients who received adjuvant chemotherapy in this study was 10.0 months, which is lower than those reported in a previous phase II clinical trial (20.8 months), a previous phase III clinical trial (15.53 months), and a previous retrospective cohort study (28.2 months). This discrepancy can be attributed to the fact that the anatomic sites of MM in the 3 aforementioned studies differed from those in this study (exclusively for patients with SNMM), and no detailed RFS outcomes were provided about either the subgroup with HNMM or that with SNMM. The prevailing belief is that disparities exist in survival outcomes among MMs of different primary sites²⁷; therefore, the findings of these studies cannot be directly compared to those of this study.

Targetable mutations are less frequently detected,²⁸ and the efficacy of chemotherapy alone is limited in MM. New therapeutics, such as ICIs used for treating MM, are promising. ICIs are well-established substances in the treatment of cutaneous melanoma (CM)²⁹ and show activity in MM as well. However, data on ICI therapy in MM are significantly less than data on its use in CM. One reason is that the SNMM subgroup is excluded in most recent prospective clinical trials. Currently, the available evidence for adjuvant ICI therapy in SNMM is based on single case reports, retrospective analyses,^21,22 and small study subpopulations in clinical trials.²³ A systematic review and meta-analysis included a total of 42 studies, 6 of which reported a combined 5-year OS rate of 42.6% after adjuvant immunotherapy.²⁴ Eleven studies reported direct comparisons between patients with SNMM who were treated with immunotherapy and those who were treated without immunotherapy; the majority (7/11) reported survival benefit for the entire cohort or select subgroups of patients with SNMM. With the transition to modern ICIs, there is a stronger trend toward survival improvement with adjuvant ICI therapy. Homoplastically, the findings of a retrospective study involving 32 patients with SNMM suggested that adjuvant ICI following carbon ion radiotherapy may be a promising treatment modality that can extend patient survival.³⁰ Additionally, a retrospective database study included 1371 patients with SNMM who received various adjuvant treatments and demonstrated that surgery with adjuvant immunotherapy, as well as surgery with adjuvant radiotherapy and immunotherapy, significantly enhanced OS compared to surgery alone.²⁵ Surgery with adjuvant radiotherapy and immunotherapy was associated with superior survival outcomes than surgery with adjuvant radiotherapy. These findings underscore the clinical benefits of incorporating adjuvant immunotherapy into the treatment regimen of patients with SNMM. Notably, the 4-year OS rate of the postoperative adjuvant radiotherapy with immunotherapy group was approximately comparable to that of the adjuvant chemoradiotherapy combined with PD-1 inhibitor group in our study. However, that database study included up to 25.1% of patients with oral MM, which is known to have significantly better OS than SNMM.³¹ Furthermore, that study solely evaluated the OS rate and did not evaluate RFS and DMFS, nor did it include data on combined adjuvant chemoradiotherapy and ICI therapy. Therefore, direct comparison of the 2 studies is not feasible. The perspective in our study, which suggests that the combination of adjuvant chemoradiotherapy and PD-1 inhibitors can significantly enhance local control in patients with SNMM, is distinctive.

Ganti et al identified advanced age and T4 stage as factors associated with a poor prognosis.⁹ Similarly, a single-arm phase II study also demonstrated that patients with T4a disease showed significantly inferior OS and DMFS to those of patients with T3 disease.²⁶ Low et al showed that the presence of regional lymph node metastasis at the time of diagnosis (N1 stage) is a negative prognostic factor for OS in cases of SNMM.³² Correspondingly, the outcome of the subgroup analysis in our study revealed that younger age, stage III disease, stage T3 disease, stage N0 disease, and lower Ki67 level at baseline are significant positive prognostic factors for SNMM, which aligns with the findings of the aforementioned studies.

We acknowledge that this study is limited by its retrospective design; hence, the statistical analyses were only exploratory. The limited sample size resulting from the rarity of SNMM posed additional constraints on this study, even though incredible efforts were made to mitigate these limitations. The confirmation of the findings of our study by a prospective randomized controlled trial is eagerly anticipated.

Conclusions

The currently recommended adjuvant therapy for SNMM is chemotherapy, optionally accompanied by local radiotherapy; however, it has suboptimal efficacy. There is increasing evidence for the efficacy of ICI therapy in patients with SNMM. Although surgery with adjuvant radiotherapy helps to provide local tumor control, local recurrence and distant metastasis are possible threats. Surgery followed by adjuvant radiochemotherapy along with a rapid initiation of adjuvant ICI may improve local control rates and could help to prevent distant metastasis. Therefore, the findings of this study present a potentially optimal adjuvant therapeutic option for SNMM and have implications for future clinical trials in this field.

Supplemental Material

sj-xlsx-1-ohn-10.1177_19160216251414150 – Supplemental material for Combination of Postoperative Adjuvant Chemoradiotherapy and Immune Checkpoint Inhibitors Significantly Prolongs Recurrence-Free Survival in Sinonasal Mucosal Melanoma

Supplemental material, sj-xlsx-1-ohn-10.1177_19160216251414150 for Combination of Postoperative Adjuvant Chemoradiotherapy and Immune Checkpoint Inhibitors Significantly Prolongs Recurrence-Free Survival in Sinonasal Mucosal Melanoma by Qiuyue Ding, Junwan Wu, Ya Ding, Dandan Li, Xizhi Wen, Hang Jiang, Linbin Chen, Qiong Zhang, Yuan Zhang, Lixia Lu, Xiaoshi Zhang and Jingjing Li in Journal of Otolaryngology - Head & Neck Surgery

Footnotes

Acknowledgements

The authors are grateful to all the patients included in the analysis and to their families for their cooperation during the telephone follow-up.

Author Contributions

XZ, JL: study design and concepts. QD, JW, YD, DL, XW, HJ, LC, QZ, YZ, LxL: data acquisition. QD, JL, JW, YD: quality control of data, algorithms, data analysis, and interpretation. QD, JjL, JW, YD, QZ: statistical analysis, manuscript preparation, and manuscript editing. QD, JW, YD contribute equally to this article. All authors read and approved the final manuscript.

Consent to Participate

Informed consent was obtained from all individual participants included in the study.

Consent for Publication

We confirm that informed consent for publication was provided by the participant(s) or a legally authorized representative.

Data Availability Statement

The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.

Declaration of Conflicting Interests

The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This work was supported by the National Natural Science Foundation of China (Grant number 82202179), the Foundation of CSCO-Junshi Tumor Immunity Research (Grant number Y-JS2019-101), and the Foundation of CSCO-Beijing Clinical Oncology Research (Grant number Y-SY201901-0156).

Ethical Considerations

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Declaration of Helsinki and its later amendments or comparable ethical standards. The study was approved by our hospital’s Institutional Review Board.

ORCID iD

Qiuyue Ding

Supplemental Material

Additional supporting information is available in the online version of the article.

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