Study sample

A total of 152 medical oncologists who had treated patients with stage III melanoma completed a survey based on their clinical experience and reviewed the charts of 507 patients diagnosed with stage III melanoma whom they had treated. Of these 507 patients, 405 (79.9%) received AT (360 received anti-PD1 therapy [222 pembrolizumab and 138 nivolumab] and 45 received BRAF/MEK therapy).

Physician survey

Physicians most frequently practiced medicine in private practice (40.1%) or in an academic institution (38.2%) and lived in the South (37.5%) or Northeast (25.0%) region. They reported having treated patients with cutaneous melanoma for a mean of 15.3 years, half of them followed > 50 stage III melanoma patients in the past 5 years, and 75.8% of their stage III melanoma patients received AT after resection.

Physicians most frequently reported clinical guidelines (61.2%), treatment efficacy (37.5%), ECOG PS (31.6%), disease stage (21.7%), and patient comorbidities (18.4%) as the key drivers of AT prescription. Most physicians (76.7%) reported that over half of their patients had available BRAF mutation status information after surgery, and 68.0% usually or always considered BRAF mutation status when offering AT to their patients. In addition, the majority (55.9%) reported that the decision to use AT was usually or always shared with patients over half of of the time. A large proportion of physicians (59.9%) reported having had a patient refuse AT. The most commons reasons for patients refusing AT were concerns about treatment-related toxicity (68.1%), expected impact on daily life and daily activities (44.0%), cost/insurance coverage (37.4%), and comorbidities (e.g., autoimmune disease) (36.3%).

Patient demographics and clinical characteristics from medical records

The mean age at the time of resection was 58.1 years, 56.0% of the patients were male, most patients were White (76.1%) and commercially insured (59.0%). At the time of resection, patients had substage IIIA (33.1%), IIIB (37.1%), or IIID (23.3%) disease (Table 1).

Table 1 Patient demographics and clinical characteristics

A total of 71.6% of patients had at least one comorbidity, and 82.0% had an ECOG PS of 0 or 1. The most common comorbidities were hypertension (38.7%), coronary artery disease/myocardial infarction (11.8%), asthma (9.5%), anxiety disorder (8.1%), and depression (7.5%; Table 1). Baseline LDH levels on the date of resection or in the preceding 6 months were obtained for 370 patients. Of these, 231 (62.4%) had normal LDH levels and 139 (37.6%) had levels that were above the upper limit of normal. In addition, BRAF mutation was found in 31.0% of the patients (Table 1). Pathological findings included ulcerations, observed in 52.9% of patients, lymphovascular invasion in 41.6%, and positive deep margins in 22.3% (Table 1).

Treatment utilization

A total of 81.6% of patients had the primary lesion resected before the main surgical resection. Most patients (92.5%) had a resection following initial melanoma diagnosis, while 6.9% had a resection following disease recurrence. The resection included a complete lymph node dissection among 74.6% of the patients, while 18.9% had sentinel node biopsy only (Supplemental Table 1, Additional File 1). After resection, 26.0% of patients received radiotherapy, either in the primary site (80.3%) or in the lymph node basin (68.9%). About 10.5% of patients received steroids after surgical resection (Supplemental Table 1, Additional File 1).

Among the 507 patients in the study, 71.0% received AT with anti-PD1, 8.9% had BRAF/MEK therapy, and 20.1% did not receive any AT (Fig. 1). Further, patients resected in recent years were significantly more likely to receive anti-PD1 therapy after resection compared to BRAF/MEK or no treatment (Supplemental Fig. 2, Additional File 1). Among patients treated with adjuvant anti-PD1 therapy, 222 (54.8%) received pembrolizumab and 138 (34.1%) received nivolumab (Table 2). The mean time from resection to treatment initiation was 37 days. Median duration of AT was 357 days, 78.4% of patients discontinued treatment, and 25 (6.2%) had a change in dosage or dose frequency (Table 2).

Table 2 Adjuvant therapy after surgical resectionReasons for AT prescription

The primary documented reasons in the patient charts for not prescribing AT included expected limited benefits of treatment (37.3%), patient’s refusal of AT (36.3%), concerns about treatment-related toxicity (30.4%), and cost/inadequate insurance coverage (25%; Fig. 2A). The documented main reasons for physicians selecting anti-PD1 therapy were to improve patient outcomes (79.2%), to limit disease progression (18.6%), patient request (13.3%), favorable cost/insurance coverage (7.5%), and high adherence (5.8%; Fig. 2B).

Fig. 2

Reasons for adjuvant therapy selection. a Reasons for not prescribing adjuvant therapy – overall and by substage. b Reasons for prescribing Anti-PD1 – overall and by substage. * P-value < 0.05. Abbreviations: LDH, lactate dehydrogenase

Determinants of treatment choices

Among all stage III patients, compared with patients who did not receive AT, having disease substages IIIB/C/D significantly increased the probability of receiving AT (odds ratio [OR] = 1.74; 95% confidence interval [CI]: 1.05, 2.89; P < 0.05). Additionally, Medicaid/no insurance (OR = 0.42, 95% CI: 0.21, 0.81; P < 0.05) and ECOG PS of 2/3 (OR = 0.37, 95% CI: 0.20, 0.70; P < 0.01) were associated with a significantly lower probability of receiving AT (Fig. 3).

Fig. 3

Determinants of adjuvant treatment choice among all patients with stage III melanoma. Abbreviations: CI, confidence interval; ECOG, Eastern Cooperative Oncology Group; LDH, lactate dehydrogenase

Subgroup analysis by substage

The mean age at the time of resection was 58.8 years for patients with stage IIIA disease and 57.8 years for patients with stage IIIB/C/D disease; 50.6% among stage IIIA patients and 58.7% among stage IIIB/C/D patients were male (Table 1).

The presence of comorbidities was similar between stage subgroups (69.6% substage IIIA and 72.6% substages IIIB/C/D). Patients with coronary artery disease/myocardial infraction were more frequent in the IIIB/C/D substage (14.2% vs. 7.1% in the stage IIIA subgroup). The proportion of patients with an ECOG PS of 0 was higher in the IIIA subgroup (39.3% vs. 29.8% in the IIIB/C/D subgroup), whereas the proportion with an ECOG PS of 1 was higher in the IIIB/C/D subgroup (52.8% vs. 41.7%; both P < 0.01; Table 1). A significantly higher proportion of patients in the IIIB/C/D subgroup had elevated levels of LDH compared to patients in the IIIA subgroup (45.6% vs. 21.3%). Patients in the IIIB/C/D substages had significantly higher proportions of ulceration, positive margin status, and lymphovascular invasion compared to patients in the IIIA substage (Table 1). Patients with stage IIIA more frequently had a resection of the primary lesion before the main surgical procedure (91.4% vs. 77.3%). No other significant differences were observed in treatment utilization between substages (Supplemental Table 1, Additional File 1).

Improving patient outcomes was a significantly more common reason for selecting anti-PD1 therapy in the stage IIIA subgroup (86.6%) compared to the IIIB/C/D subgroup (75.8%; Fig. 2B). Meanwhile, favorable cost/insurance coverage was a more common factor for anti-PD1 therapy selection among patients in the IIIB/C/D subgroup (9.7%) compared to patients in the IIIA subgroup (2.7%; Fig. 2B).

The multivariable regression analysis identified several factors associated with adjuvant treatment choice stratified by disease substage. For patients with stage IIIA disease, SLN biopsy (OR = 23.63, 95% CI: 3.29, 169.94; P < 0.01) and CLND (OR = 5.52, 95% CI: 1.10, 27.70; P < 0.05 vs. elective dissection), and baseline LDH levels above the upper limit of normal (OR = 4.46, 95% CI: 1.06, 18.75; P < 0.05) were associated with a significantly higher probability of receiving AT. Medicaid/no insurance status (OR = 0.13, 95% CI: 0.04, 0.42; P < 0.001), ECOG PS of 2/3 (OR = 0.27, 95% CI: 0.08, 0.90; P < 0.05), and receipt of steroids (OR = 0.23, 95% CI: 0.06, 0.90; P < 0.05) were associated with a significantly lower probability of receiving AT (Supplemental Fig. 3, Additional File 1). For patients with stage IIIB/C/D disease, ECOG PS of 2/3 (OR = 0.28, 95% CI: 0.14, 0.57; P < 0.001), treatment after resection for disease recurrence (OR = 0.38, 95% CI: 0.14, 0.98; P < 0.05 vs. treatment at initial resection), and receipt of radiotherapy after resection (OR = 0.50, 95% CI: 0.27, 0.93; P < 0.05) were associated with a significantly lower probability of receiving AT (Supplemental Fig. 4, Additional File 1).

Subgroup analysis by treatment category

Patients in each treatment group had mean age of approximately 58 years, and the proportion of males was numerically higher among not treated patients (65.7% vs. 54.2% in the anti-PD1 subgroup, and 48.9% in the BRAF/MEK subgroup). The subgroup of not treated patients had a significantly lower proportion of commercially insured patients and higher proportion of Medicaid patients compared to the anti-PD1 and BRAF/MEK subgroups. About 17.7% of patients in the not treated group had stage IIIB/C/D disease compared with 32.0% in the anti-PD1 therapy subgroup and 40.0% in the BRAF/MEK therapy subgroup (P < 0.01; Table 1). Patients in the not treated group were significantly more likely to have higher ECOG PS (e.g., 30.4% of these patients had an ECOG PS of 2/3 compared with 10.0% in the anti-PD1 therapy subgroup and 6.7% in the BRAF/MEK therapy subgroup; P < 0.001; Table 1).

Regarding treatment utilization, the proportion of patients who received radiotherapy after resection was significantly higher among not treated patients (37.3%) compared to patients who received anti-PD1 (22.2%) or BRAF/MEK therapy (31.1%).

The multinomial logistic regression model identified several factors associated with AT choice (anti-PD1 or BRAF/MEK therapy vs. no AT; Table 3). Compared with patients who did not receive AT, stage IIIB/C/D disease was associated with a significantly higher probability of receiving treatment with anti-PD1 therapy (OR = 1.82, 95% CI: 1.09, 3.05; P < 0.05). Additionally, Medicaid/no insurance status (OR = 0.43, 95% CI: 0.22, 0.84; P < 0.05), ECOG PS of 2/3 (OR = 0.41, 95% CI: 0.22, 0.79; P < 0.01), and history of coronary artery disease/myocardial infarction (OR = 0.49, 95% CI: 0.24, 0.98; P < 0.05) were associated with a significantly lower probability of receiving anti-PD1 therapy. ECOG PS of 2/3 (OR = 0.16, 95% CI: 0.04, 0.63; P < 0.01) was also associated with a significantly lower probability of receiving adjuvant BRAF/MEK therapy.

Table 3 Determinants of adjuvant treatment choice stratified by AT type