
==== Front
Target Oncol
Target Oncol
Targeted Oncology
1776-2596
1776-260X
Springer International Publishing Cham

39182000
1090
10.1007/s11523-024-01090-9
Original Research Article
lnsights into Adjuvant Systemic Treatment Selection for Patients with Stage III Melanoma: Data from the Dutch Cancer Registry
http://orcid.org/0000-0002-6639-1601
Aldenhoven Loeki l.aldenhoven@zuyderland.nl

1
van Weezelenburg Merel A. Spiekerman 1
van den Berkmortel Franchette W. P. J. 2
Servaas Nick 1
Janssen Alfred 1
Vissers Yvonne L. J. 1
van Haaren Elisabeth R. M. 1
Beets Geerard L. 34
van Bastelaar James 1
1 https://ror.org/03bfc4534 grid.416905.f Department of Surgery, Zuyderland Medical Center, P.O. Box 5500, 6130 MB Sittard-Geleen, The Netherlands
2 https://ror.org/03bfc4534 grid.416905.f Department of Medical Oncology, Zuyderland Medical Center, Sittard, The Netherlands
3 https://ror.org/03xqtf034 grid.430814.a 0000 0001 0674 1393 Department of Surgery, Netherlands Cancer Institute, Amsterdam, The Netherlands
4 https://ror.org/02jz4aj89 grid.5012.6 0000 0001 0481 6099 GROW-School for Oncology and Developmental Biology, Maastricht University, Maastricht, The Netherlands
24 8 2024
24 8 2024
2024
19 5 735745
2 8 2024
© The Author(s) 2024
2024
https://creativecommons.org/licenses/by-nc/4.0/ Open Access This article is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License, which permits any non-commercial use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by-nc/4.0/.
Background

Patient demographics and shared decision making might influence the choice of adjuvant therapy for stage III melanoma.

Objective

To identify factors for treatment selection of patients diagnosed with stage III melanoma to better understand current treatment decisions and improve further treatment counseling.

Patients and Methods

Data from 2007 patients diagnosed with stage III melanoma, between December 2018 and 2021, sourced from the Dutch Cancer Registry, were analyzed.

Results

Among the cohort, 48.7% received no therapy, 45.8% received checkpoint inhibition, and 5.5% received targeted therapy (TT). Patients foregoing therapy were significantly older [67.0 years (range 53.0–77.0) vs. 62.0 year (range 52.0–72.0)], had poorer performance scores (PS), and higher Charlson Comorbidity Index scores compared to those receiving therapy (p < 0.001). Patients undergoing therapy had significantly higher median Breslow thickness (3.3 mm vs. 2.2 mm) and higher prevalence of ulceration (49.9% vs. 38.1%). Those with connective tissue disease and/or congestive heart disease were more likely to receive TT [odds ration (OR) 8.1; 95% confidence interval (CI) 1.7–37.6 and OR 9.3; 95% CI 1.2–72.2, respectively]. Median treatment time among strata for disease recurrence was 4.26 months (3.69–4.82) for immunotherapy and 3.1 months (0.85–5.36) for TT (p = 0.298). Patients who developed recurrent disease were equal across treatment types (p = 0.656). The number of patients with grade 3 complications was different for each treatment type [immunotherapy: 17.8% vs. TT: 37.3% (p < 0.001)].

Conclusions

Age, PS, and Breslow thickness seem to influence adjuvant treatment decisions. Clinicians’ preference for immunotherapy might play a role in counseling BRAF-positive patients for adjuvant therapy, this however, cannot be confirmed in this dataset. Overall, only a small proportion of patients completed adjuvant treatment.

issue-copyright-statement© Springer Nature Switzerland AG 2024
==== Body
pmcKey Points

Patients are counseled to some extent.	
Understanding patient counseling is challenging due to the shared decision-making process.	
Clinicians’ preference for immunotherapy might play a role in counseling BRAF-positive patients for adjuvant therapy.	

Introduction

Accurate staging of cutaneous melanoma is a fundamental cornerstone for prognostic assessment, clinical decision making, and establishing adjuvant treatment plans for stage III (and resected stage IV) melanoma patients [1]. Although promising results from several randomized controlled trials have led to registration of a selected group of drugs for adjuvant treatment for patients with stage III melanoma [2], optimal treatment strategies are still open for debate [2–11].

The European Medicine Agency (EMA) has approved different checkpoint inhibitors for the adjuvant treatment of stage III cutaneous melanoma in the European Union. More specifically, the Medicine Evaluation Board (MEB (CBG in Dutch) cooperates with EMA regarding medicines available in the Netherlands. Both EMA and MEB approved two checkpoint inhibitors in the adjuvant setting: nivolumab—PD-1 (Opdivo®) [12, 13] and pembrolizumab—D-1 (Keytruda®) [12, 14]. Targeted therapy (TT) options include one BRAF inhibitor, dabrafenib (Tafinlar®) [12, 13] and one MEK inhibitor, trametinib (Mekinist®) [12, 13].

Current scientific evidence has demonstrated a prolonged disease-free survival after adjuvant systemic therapy [15]. Melanoma-specific survival for patients who received systemic treatment was 28.3 months [95% confidence interval (CI) 28.3–NR] [16]. However, the effect of adjuvant regimens on long-term overall survival has yet to be proven [17]. Additionally, overall survival rates have to be interpreted with caution due to interference of subsequent treatment regimens in the adjuvant setting [2]. The definitive choice of therapy may be based on several patient characteristics, clinical characteristics, and pathological tumor characteristics such as molecular test results, toxicity profiles, patients’ preferences, and route of administration [18]. Figure 1 depicts a flowchart of therapy strategies according to Dutch guidelines. Patients with stage IIIA (SLN tumor burden ≥ 1 mm), IIIB, IIIC, and resected stage IV melanoma are candidates for adjuvant checkpoint inhibition with nivolumab or pembrolizumab for 1 year, with or without a BRAF mutation. Only patients with a BRAF mutation are candidates for TT, dabrafenib combined with trametinib, for the duration of 1 year. For stage IIIB and IIIC, both TT and checkpoint inhibition are viable options [12]. Shared decision making might possibly influence the choice for treatment and the type of adjuvant systemic therapy. The Dutch melanoma guideline for adjuvant therapy recommends counseling patients with stage III melanoma and a BRAF mutation about whether to start therapy, with either TT or immunotherapy [12]. Patients should be informed about all the (dis)advantages and particulars of each drug or each drug combination. Current guidelines recommend counseling for adjuvant therapy of all patients with evidence of nodal involvement or resectable regional or distant metastasis.Fig. 1 Flowchart treatment choices for stage III melanoma patients. IIIA = SLN tumor burden ≥ 1 mm

This counseling may, however, result in variations in treatment regimens among oncologists, hospitals, and melanoma expertise centers [19]. Hence, this study aimed to describe the number of stage III patients receiving adjuvant immunotherapy or TT in relation to patients’ demographics. Additionally, this study aimed to gain more insight into potential factors that influence decision making. Furthermore, additional data regarding preliminary discontinuation have been collected in order to gather more insight into causes of early discontinuation of treatment and ultimately improve the shared decision-making process.

Material and Methods

Study Population

In this retrospective study, data of adult (≥ 18 years of age) patients diagnosed with resected stage III cutaneous melanoma between December 2018 and December 2021 were retrieved form the Netherlands Cancer Registry (NCR). The NCR comprises information on demographics and tumor characteristics of all newly diagnosed cancer patients in the Netherlands, irrespective of type and expertise of hospitals. Data were extracted from electronic patient records by well-trained registration employees of the Netherlands comprehensive cancer organization (IKNL). All study patients were staged according to the guidelines of the American Joint Committee on Cancer (AJCC) 8th edition. Data selection was based on the “International Classification of Diseases for Oncology” (ICD-O-Category C44).

Statistics

Patient demographics and histological/pathological characteristics were described in detail. Continuous variables were reported as means and standard deviations (SDs) or, in case of severe skewness, as median and interquartile range (IQR). Categorical variables were reported as counts and percentages. Percentages were calculated using the total group, including missing cases. Patients were divided into two groups based on the chosen adjuvant treatment strategy. Subsequently, patients were divided into groups based on BRAF mutation (BRAF + and BRAF unknown) as in these patients the counseling process regarding the choice of therapy is important. Data regarding patients receiving immunotherapy or patients receiving TT were retrieved. All group characteristics were described in detail and compared where appropriate. Early discontinuation was calculated from the date of initial start of therapy until stopping prior to the stop date as described per protocol. Time to early discontinuation was analyzed using Kaplan-Meier curves and compared using the log rank test with a significance level of 0.05. IBM Statistical Package for Social Sciences (SPSS) (version 26) was used for statistical analyses.

Multinomial logistic regression was performed in order to define predicting variables for receiving any form of adjuvant therapy. Additionally, multinomial logistic regression was performed in order to define predicting variables for receiving either immunotherapy or TT in patients with a BRAF mutation and unknown BRAF mutation.

Results

Patients

In total, 2007 patients with stage III melanoma were included in this study. Of these patients, 977 (48.7%) patients received no adjuvant systemic treatment, 920 (45.8%) patients received checkpoint inhibitors as initial adjuvant therapy, and 110 (5.5%) patients received TT as initial therapy. Characteristics of all patients are described in Table 1. Table 1 Characteristics of patients receiving no therapy or adjuvant therapy

Characteristic	N = 977	N = 1030	P value	
No adjuvant therapy	Adjuvant therapy	
Age in years (median (IQR))	67.0 (53.0–77.0)	62.0 (52.0–72.0)	0.000*	
Gender (n (%))		
 Male	517 (52.9%)	642 (62.3%)	0.000*	
 Female	460 (47.1%)	388 (37.7%)	
Performance status (n (%))		
 WHO ≤1	280 (28.7%)	767 (74.5%)	0.000*	
 WHO ≥2	40 (4.1%)	13 (1.3%)	
 Unknown	657 (67.2%)	250 (24.3%)	0.000*	
Tumor characteristics	
 Histological subtype (n (%))		
  SSMM	655 (67.0%)	579 (56.2%)	0.000*	
  Nodular	214 (21.9%)	298 (28.9%)	
  Acral lentiginous	24 (2.5%)	39 (3.8%)	
  Lentigo maligna#	13 (1.3%)	14 (1.4%)	
  Desmoplastic	5 (0.5%)	5 (0.5%)	
  Other/unknown	66 (6.8%)	95 (9.2%)	
 Breslow thickness (median (IQR))	2.2 (1.4–4.1)	3.3 (2.0–5.2)	0.000*	
 Ulceration (n, %)	362 (38.1%)	496 (49.9%)	0.000*	
 SN-procedure (n, %)	796 (81.5)	805 (78.2%)	0.064	
 Lymph nodes status (pN) (n, %)		
  1A	619 (63.4%)	462 (44.9%)	0.000*	
  1B	22 (2.3%)	41 (4.0%)	0.024*	
  1C	137 (14.0%)	102 (9.9%)	0.005*	
  2A	96 (9.8%)	170 (16.5%)	0.000*	
  2B	12 (1.2%)	55 (5.3%)	0.000*	
  2C	26 (2.7%)	75 (7.3%)	0.000*	
  3A	3 (0.3%)	10 (1.0%)	0.062	
  3B	16 (1.6%)	35 (3.4%)	0.011*	
  3C	25 (2.6%)	50 (4.9%)	0.006*	
 Clinical stage (n, (%))	
  IIIA	382 (39.1%)	141 (13.7%)	0.000*	
  IIIB	233 (23.8%)	290 (28.2%)	0.028*	
  IIIC	343 (35.1%)	561 (54.5%)	0.000*	
  IIID	19 (1.9%)	38 (3.7%)	0.019*	
 BRAF mutation (n, (%))	155 (15.9%)	445 (43.2%)	0.000*	
 BRAF mutation unknown (n, (%))	662 (67.8%)	102 (9.9%)	0.000*	
 Comorbidities ≥1 (n, (%))	352 (35.3%)	281 (27.3%)	0.001*	
 Comorbidities unknown (n, (%))	97 (9.7%)	101 (9.8%)	0.927	
 Charlson Comorbidity Index (median (IQR))	3.0 (1.0–4.0)	2.0 (1.0–3.0)	0.000*	
IQR interquartile range, WHO World Health Organization, SSMM superficial spreading melanoma

*Statistically significant

#Potential regression of primary tumor

The performance score was used to categorize patients into one of the two WHO Performance Status (PS) groups: those with either a “good” (≤ 1) or a “poor” (≥ 2) PS.

No Therapy Versus Adjuvant Therapy

Patients who received no adjuvant treatment were significantly older than patients receiving adjuvant therapy (p < 0.001), and there were more male patients receiving therapy when compared to female patients (p < 0.001). The data suggest that PS and adjuvant therapy were associated, with patients receiving no therapy presenting with a poorer WHO PS compared to patients receiving adjuvant therapy (p < 0.001). This is reflected in the Charlson Comorbidity Index (CCI). The median CCI was higher in patients who did not receive adjuvant therapy when compared to patients receiving adjuvant treatment [3.0 (1.0–4.0) vs. 2.0 (1.0–3.0) (p = 0.000)]. There were significantly more patients with comorbidities in the no-therapy group compared to patients receiving adjuvant therapy. Additionally, the median Breslow thickness was significantly thicker in patients receiving adjuvant therapy when compared to patients without therapy [3.3 mm (2.0–5.2) vs. 2.2 mm (1.4–4.1), p < 0.001]. Ulceration was significantly more present in patients receiving treatment (38.1% vs. 49.9%). Furthermore, more patients receiving systemic therapy were found to have more elaborate nodal involvement when compared to patients not receiving therapy.

Melanoma Expert Center Versus Non-Expert Center

Fifty-seven percent (553/977) of patients not receiving adjuvant treatment were not assessed in a melanoma center. However, for 48.6% (284/553) of these patients an expert center was consulted. Twenty-nine percent (284/977) of patients not receiving therapy were neither assessed in a melanoma expert center nor discussed with expert centers. The data suggest that being assessed at a non-expert center does not seem to affect the likelihood of receiving therapy (29% vs. 43% in melanoma expert centers). All patients who received adjuvant treatment were treated in a melanoma expert center. Reasons for waiving treatment were reported for only 16.2% of the patients. Reasons for waiving treatment were: patient’s or family choice (9.5%); comorbidities, poor PS or functional status (4.0%); minor tumor load (2.5%); high tumor load, disease progression, or disease end-stage (0.2%); reason unknown (83.8%).

Immunotherapy Versus Targeted Therapy

A BRAF mutation was confirmed in 445 (43.2%) patients receiving adjuvant therapy. In this group, 345 patients (77.5%) received immunotherapy and 100 patients (22.5%) received TT. Patient and tumor characteristics in patients with a BRAF mutation were equally distributed across treatment groups. Analyzing specific comorbidities, the difference in occurrence of connective tissue diseases between treatment groups in the BRAF population was statistically significant. This group of diseases includes systemic lupus erythematosus, Sjögrens, dermatomyocitis, polymyositis, rheumatoid arthritis or other inflammatory polyarthropathies, polymyalgia rheumatica, systemic sclerosis, or other specified diffuse diseases of connective tissue [20]. Patients with connective tissue disease received TT more frequently than immunotherapy (5.1% vs. 0.6%, p = 0.002). No patients with dementia received adjuvant therapy.

Immunotherapy Versus Targeted Therapy—BRAF Mutation

A BRAF mutation was found in 37.5% of the patients receiving immunotherapy and in 90.9% receiving TT (p < 0.001). In the treatment period, a grade 3 complication was registered for 95/533 (17.8%) patients in the immunotherapy group and 25/67 (38.5%) patients in the TT group (p < 0.001). However, complication registration was unknown for 430 (41.7%) patients. When analyzing grade 3 complications in BRAF-mutated patients, there were 35 patients with a grade 3 complication in the immunotherapy group. None of them switched to TT. In the TT group, 25 patients had a grade 3 complication. Two of these 25 patients (8.0%) switched from TT to immunotherapy.

Figure 2 represents the treatment allocation per stage and BRAF mutation. There were substantially more patients with an unknown BRAF mutation who did not receive any form of adjuvant therapy. These patients were possibly unfit for any form of adjuvant treatment, thus leading to the omission of molecular analysis. Stage IIIA patients were less likely to receive adjuvant therapy. Most patients receiving adjuvant therapy were treated with immunotherapy (Table 2).Fig. 2 Treatment allocation per stage and BRAF mutation

Table 2 Characteristics of patients with BRAF mutation and unknown BRAF mutation receiving adjuvant systemic therapy

Mutation	BRAF +	BRAF unknown	
	N = 345	N = 100		N = 285	N = 9		
Characteristic	Immunotherapy	Targeted therapy	P value	Immunotherapy	Targeted therapy	P value	
Age in years (median (IQR))	59.0 (48.0–70.0)	58.2 (48.3–68.0)	0.710	63.0 (53.0–71.5)	60.0 (38.0–72.0)	0.917	
Gender (n (%))		
 Male	213 (61.7%)	57 (57.0%)	0.393	166 (58.2%)	8 (88.9%)	0.066	
 Female	132 (38.3%)	43 (43.0%)	119 (41.8%)	1 (11.1%)	
Performance status (n (%))		
 WHO ≤ 1	294 (85.2%)	80 (80.0%)	0.173	146 (51.2%)	0 (0.0%)	–	
 WHO ≥ 2	4 (1.2%)	3 (3.0%)	1 (0.4%)	0 (0.0%)	
 Unknown	47 (13.6%)	17 (17.0%)	0.397	138 (48.4%)	9 (100.0%)	0.002*	
Tumor characteristics	
 Breslow thickness (median (IQR))	2.9 (1.8–5.1)	3.1 (1.8–6.0)	0.613	3.1 (2.1–4.8)	6.1 (5.4–26.5)	0.035	
 Ulceration (n, %)	160 (46.4%)	41 (41.0%)	0.546	140 (49.1%)	6 (66.7%)	0.358	
 Lymph nodes status (pN) (n, %)		
  1A	147 (42.6%)	46 (46.0%)	0.284	134 (47.0%)	4 (44.4%)	0.768	
  1B	14 (4.1%)	3 (3.0%)	0.695	10 (3.5%)	0 (0.0%)	0.557	
  1C	27 (7.8%)	4 (4.0%)	0.228	30 (10.5%)	1 (11.1%)	0.997	
  2A	66 (19.1%)	15 (15.0%)	0.472	51 (17.9%)	1 (11.1%)	0.150	
  2B	25 (7.2%)	4 (4.0%)	0.297	11 (3.9%)	1 (11.1%)	0.304	
  2C	26 (7.5%)	10 (10.0%)	0.336	18 (6.3%)	1 (11.1%)	0.600	
  3A	6 (1.7%)	0 (0.0%)	0.197	2 (0.7%)	1 (11.1%)	0.003*	
  3B	10 (2.9%)	5 (5.0%)	0.255	5 (1.8%)	1 (11.1%)	0.059	
  3C	19 (5.5%)	6 (6.0%)	0.752	10 (3.5%)	0 (0.0%)	0.557	
 Clinical stage (n, (%))	
  IIIA	60 (17.4%)	17 (17.0%)	0.927	35 (12.3%)	1 (11.1%)	0.916	
  IIIB	95 (27.5%)	27 (27.0%)	0.916	92 (32.3)	0 (0.0%)	0.040*	
  IIIC	178 (51.6%)	52 (52.0%)	0.943	150 (52.6%)	8 (88.9%)	0.032*	
  IIID	12 (3.5%)	4 (4.0%)	0.805	8 (2.8%)	0 (0.0%)	0.610	
 Comorbidities ≥1 (n, (%))	83 (24.3%)	26 (26.0%)	0.696	61 (21.4%)	0 (0.0%)	0.507	
 Comorbidities unknown (n, (%))	4 (1.2%)	1 (1.0%)	0.849	85 (29.8%)	8 (88.8%)	< 0.001*	
 Charlson Comorbidity Index (median (IQR))	2.0 (0.0–3.0)	2.0 (1.0–3.0)	0.602	2.0 (1.0–3.0)	0.0 (0.0–0.0)	0.159	
IQR interquartile range; WHO World Health Organization

*Statistically significant

–Cannot be estimated

Predicting Variables

Older patients were less likely to receive adjuvant treatment (OR 0.97; 95% CI 0.96–0.99) (p < 0.001). The likelihood of receiving adjuvant treatment tends to increase with increasing Breslow thickness (OR 1.03; 95% CI 1.00–1.08) (p = 0.06). Additionally, the presence of ulceration seems to significantly affect the choice for adjuvant therapy, OR 1.35; 95% CI 1.02–1.80 (p = 0.038). The same applied to the stage of nodal involvement. Worsening nodal involvement increased the likelihood for receiving adjuvant therapy. The odds ratio for receiving adjuvant therapy with an N2 status is 2.32; 95% CI 1.62–3.32 (p < 0.001) and 2.36; 95% CI 1.32–4.22 (p = 0.004) for N3 status when compared to reference N1 status. Patients with a poor PS were less likely to receive treatment (OR 0.07; 95% CI 0.03–0.16) (p < 0.001).

Considering the CCI score, age will be omitted from the multinomial logistic regression model as it is incorporated in the CCI score. The CCI score significantly affected the choice for adjuvant therapy, OR 0.82; 95% CI 0.76–0.88 (p < 0.001). However, adding age and CCI score (without correcting for age) separately to the model, the CCI score did not significantly affect the choice for treatment anymore [OR 0.91; 95% CI 0.80–1.05 (p = 0.186)].

It was more likely that patients received TT if a BRAF mutation was present (OR 109.65; 95% CI 14.60–823.18). Patients with a BRAF mutation, connective tissue disease, and/or congestive heart failure were more likely to be allocated to treatment with targeted therapy (OR 8.09; 95% CI 1.74–37.57 and OR 9.33; 95% CI 1.21–72.23). The CCI score does not seem to affect the choice for the type of treatment (OR 0.88; 95 CI 0.75–0.91). In case of unknown BRAF mutation (n = 9), only Breslow thickness was of predictive value. Patients with thicker melanomas were more likely to receive TT, even when BRAF mutation status was unknown (OR 1.1; 95% CI 1.06–1.23).

Early Discontinuation of Treatment

Treatment duration for both immunotherapy and TT is 52 weeks [12]. However, the first cycle of therapy starts at timepoint 0. Hence, effective treatment is 48 weeks. Early discontinuation was defined as the end of treatment more than 1 month before the stop date as described per protocol. Complete data only (73.5% of the patients) were used to calculate time to end of treatment. Figure 3 presents the time to end of treatment for both immunotherapy and TT. Median treatment time for immunotherapy was 6.50 months (5.50–7.51) and 4.03 months (2.26–5.79) for TT without any statistically significant differences (p = 0.268). Table 3 shows the number of patients who completed or discontinued treatment. The number of patients who completed treatment was not significantly different across treatment types (p = 0.905). There were significantly more patients in the TT group in which the treatment stop date was unknown (p = 0.013).Fig. 3 Kaplan–Meier. Time to discontinuation of treatment for both immunotherapy and targeted therapy

Table 3 Number of patients who completed treatment or discontinued treatment (complete data only)

	Immunotherapy (N = 687)	Targeted therapy (N = 70)	P value	
Treatment completed	260 (37.8%)	27 (38.6%)	0.905	
Early discontinuation	427 (62.2%)	43 (61.4%)	
Unknown stop date	232/920 (25.2%)	40/110 (36.4%)	0.013*	

Patients receiving immunotherapy were more likely to discontinue treatment due to grade 3 complications (OR 5.62; 95% CI 2.97–10.63) when compared to patients without grade 3 complications. Patients receiving TT who experienced grade 3 complications had increased odds of discontinuing TT, when compared to patients receiving TT without grade 3 complications, albeit not significant (OR 2.68; 95% CI 0.70–10.29). The number of patients who developed grade 3 complications were significantly different for each treatment type [immunotherapy: 17.8% vs. TT: 37.3% (p < 0.001)].

Patients receiving immunotherapy were more likely to discontinue treatment due to recurrent disease (OR 3.63; 95% CI 2.32–5.68) when compared to patients without recurrent disease. Patients receiving TT with recurrent disease had increased odds of discontinuing TT, when compared to patients receiving TT without recurrent disease, though not significant (OR 1.89; 95% CI 0.68–5.23). The number of patients who develop recurrent disease were equal across treatment types [immunotherapy: 26.5% vs. TT: 24.5% (p = 0.656)].

Figure 4 presents the time to end of treatment for both immunotherapy and TT among strata for disease recurrence. Median treatment time for immunotherapy was 4.26 months (3.69–4.82) and 3.1 months (0.85–5.36) for TT without any statistically significant differences (p = 0.298).Fig. 4 Kaplan–Meier. Time to discontinuation of treatment for both immunotherapy and targeted therapy among strata for disease recurrence

Discussion

Since the introduction of TT and immunotherapy for melanoma patients in December 2018, adjuvant treatment regimens have been continuously evolving. The indications and clinical outcomes vary for both treatment modalities [21]. No head-to-head trial of resected stage III adjuvant treatment between dabrafenib–trametinib and anti-PD1 exists; however, the hazard ratios of recurrence in these trials of systemic therapy versus placebo in KEYNOTE-054 [6] and COMBI-AD [11] were very similar, suggesting comparable risk reduction of the two types of treatment [6, 11]. Therefore, counseling patients is essential in the shared decision-making process after surgical treatment. To better understand current treatment decisions and improve further treatment counseling, this retrospective data analysis aimed to elucidate which factors were associated with the counseling process and identify possible motives for treatment selection of patients diagnosed with stage III melanoma.

One of the first distinguishing factors when considering adjuvant treatment options is patients’ age. Consistent with previously published studies, age does affect opting in or out of adjuvant therapy [22–24]. There could be several explanations for the association between treatment choice and age. With age, the frequency of co-morbidities generally increases, PS declines, and even the burden regarding hospital visits might play a role [24]. Previous research has shown that response to BRAF inhibitors may be attenuated in older patients (> 60 years) and that these patients have improved outcomes with immunotherapy rather than TT [25–27]. The mean age of patients receiving treatment in this study was 60 years and the age of patients eligible for counseling (BRAF+ and BRAF unknown) was equal in both treatment groups. Therefore, this study can neither confirm nor reject whether age was a consideration when counseling patients for the type of adjuvant therapy. None of the patient characteristics or tumor characteristics were statistically significant between the two treatment groups in BRAF+ patients. The large majority of BRAF+ patients received immunotherapy.

As nearly all available therapies might cause potentially serious toxicities, one of the most important factors to be considered is patients’ PS. Patients with a poor PS are vulnerable and show less favorable treatment outcomes [28]. The study data confirm PS as a distinguishing factor as patients receiving therapy have a better PS compared to patients receiving no therapy. After opting for any form of therapy, PS was no longer a determining factor for type of therapy administered.

The comorbidities of some patients receiving adjuvant therapy were unknown. Consideration of pre-existing autoimmune diseases is advised in the literature as these diseases can flare up with immunotherapy [29, 30]. Additionally, the occurrence of cardiotoxicity seems to be higher with immunotherapy compared with TT [31]. Consideration of pre-existing autoimmune diseases and heart failure is part of the counseling process. TT is preferred in patients with connective tissue disease and congestive heart disease. In addition, the CCI was significantly different in patients receiving adjuvant therapy versus patients without therapy. This is in line with the findings regarding PS. Remarkably, CCI alone was a significant predictive factor for receiving adjuvant therapy in the regression analysis. However, if age was used separately and the CCI was not corrected for age, the CCI was not significantly important anymore. This suggests that age is the most important contributing factor in the CCI, again proving the point that age is a complex and interlinked factor influencing multiple aspects of the shared decision-making process.

Aside from patient characteristics, several tumor characteristics are considered in the treatment allocation process. Nodal involvement and Breslow thickness seems to have a significant impact on the decision to administer adjuvant therapy. This result could possibly be explained by the progressive association of Breslow thickness and worse prognosis [32]. As TT is exclusively approved for patients with BRAF mutation [2, 11, 12], it is obvious that the presence of a BRAF mutation plays a leading role in treatment decisions. However, the majority of patients with a BRAF mutation opting for adjuvant therapy received immunotherapy and none of the other factors were associated with treatment choice. Highly esteemed studies, such as the KEYNOTE-054 trial [33], the CheckMate 238 [34] and 915 trials [35], and the COMBI-AD trial [36] investigated the efficacy and safety of different types of treatment regimens on disease-free survival. These studies are, however, heterogenous, as monotreatment was compared to placebo or a combination of anti PD-1 with CTLA-4 inhibition was compared to anti PD-1 therapy only. Study findings have not provided conclusive evidence favoring one therapy over the other in the adjuvant setting. Furthermore, direct comparison between checkpoint inhibition and TT in patients with a BRAF mutation was not performed. However, the DREAMseq Trial studied the efficacy of the initial treatment sequence in patients with metastatic melanoma. Checkpoint inhibition followed by BRAF/MEK inhibitor therapy was found to be the preferred treatment sequence. These study results might influence medical oncologists’ preferences, opting for checkpoint inhibition as first-line treatment [21]. This would support the results of this study as the majority of patients received immunotherapy. Additionally, this DREAMseq reasoning would explain the discrepancy between the results of this study and those of the Italian EAP study [37] and the German DeCOG study [38] for stage IIIB-D melanoma.

It is remarkable that some patients received TT without a BRAF mutation. With limited detailed information in the dataset, the reasons for this could not be found. This could be considered as a limitation of the dataset, either by imputing incorrect information or by not providing enough information regarding this data. Moreover, in a large proportion of patients who did not receive adjuvant therapy, the BRAF status was unknown. As mentioned previously, these patients were possibly unfit for any form of adjuvant treatment thus leading to the omission of molecular analysis.

In general, immunotherapy appears to be well tolerated when compared to TT. This is in line with other scientific reports regarding grade ≥ 3 complications, reporting incidences between 13% and 18% for immunotherapy and 12% and 41% for TT [6, 11, 17, 39]. Generally, immunotherapy can be continued in case of grade 1 or 2 toxicity with close monitoring (not reported in the NCR) while treatment should be suspended in case of grade ≥ 3 toxicities [40]. TT-induced toxicities are often related to drug exposure and might resolve on discontinuation of treatment [17]. It is remarkable that none of the patients with a BRAF mutation who discontinued immunotherapy switched to TT since TT-related toxicities resolve easily by stopping drug administration [21].

A reason for discontinuation of targeted treatment is disease progression during therapy. Patients receiving TT discontinue treatment earlier in case of recurrent disease when compared to patients in the immunotherapy group. In the Netherlands, medical imaging is generally performed every 3–4 months to evaluate stages of disease. Checkpoint inhibitors do not directly induce antitumor effects, therefore efficacy of immunotherapy will only be noticeable after several cycles. Suspected lesions in the early phase of immunotherapy should be reassessed. Direct discontinuation is not recommended in patients with immunotherapy [41, 42]. This is not described for patients receiving TT. Therefore, recurrence in patients with TT may lead to direct discontinuation of treatment.

The retrospective design of this study has certain limitations. Data were retrieved from the Dutch cancer registry, which is thoroughly screened by data analysts to minimize incorrect or incomplete information in medical records. Detailed information about patient preferences or treatment-related toxicities was lacking. Additionally, nivolumab, ipilimumab, and pembrolizumab were covered by basic health insurance in the Netherlands as of 11 November 2018. Until August 2019, dabrafenib and trametinib were placed in package lock for expensive medicinal products, though the oncologic drugs advisory committee had given a positive advice on this combined treatment. Therefore, until August 2019 the number of patients was most probably biased as TT was administered for research purposes. Nevertheless, this paper might provide us with a better understanding of reasons used for adjuvant therapy counseling.

Conclusion

These data suggest that patients are to some extent being counseled before receiving adjuvant therapy, since age, PS, and Breslow thickness seem to influence this decision. However, understanding counseling motives is challenging as patients’ age is a complex factor. Age is presumably indirectly related to PS and comorbidities. It seems likely that counseling patients with a BRAF mutation can be optimized, as the majority of these patients received immunotherapy. Patient’s preferences and the role of the medical oncologist were understudied due to lack of data. Clinicians’ preference for immunotherapy might play a role in counseling BRAF-positive patients for adjuvant therapy, however, this cannot be confirmed in this dataset. Finally, this study shows that only a small proportion of all patients with melanoma stage III completed full adjuvant treatment regimens.

Declarations

Funding

No external funding was used in the preparation of this article.

Conflict of interest

Loeki Aldenhoven, Merel A. Spiekerman van Weezelenburg, Franchette W.P.J. van den Berkmortel, Nick Servaas, Alfred Janssen, Yvonne L.J. Vissers, Elisabeth R.M. van Haaren, Geerard L. Beets, and James van Bastelaar declare that they have no conflicts of interest that might be relevant to the contents of this article.

Ethics approval

Not applicable.

Availability of data, codes, and material

The datasets generated and/or analyzed during the current study are not publicly available for reasons of sensitivity but are available from the corresponding author on reasonable request.

Author contributions

All authors contributed to the study conception and design. Material preparation, data collection, and analysis were performed by Loeki Aldenhoven. The first draft of the manuscript was written by Loeki Aldenhoven and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.

Consent

IKNL may only provide data from the NCR if it is used for scientific research or statistics (e.g., epidemiology). This has been contractually agreed with the hospitals that supply a large part of the NCR data. Anyone who wishes to use data for research purposes must submit a request for this. An independent committee—the NCR’s Supervisory Committee—then determines whether the data can be supplied. Patients are also among the members of this Committee. The data provided will be anonymous. This means that the researchers using the data will not know whose data it involves.
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