Treatment at the end of life in patients with advanced melanoma. A multicenter DeCOG study of 1067 patients from the prospective skin cancer registry ADOReg

Background: Although systemic therapies have improved considerably over the last decade, up to 50% of patients with metastatic melanoma still die due to disease progression. Oncological treatment at the end-of-life phase is challenging. The aim of this study was to investigate the frequency and type of systemic therapy received by melanoma patients in their end-of-life phase.

Methods: Patients with metastatic melanoma who had died between January 1, 2018 and October 31, 2022 were identified from the prospective multicenter skin cancer registry ADOReg. Study endpoints were percentage of patients who had been treated with systemic therapy within the last three months of life, timepoint of initiation of the last-line therapy, overall survival, treatment benefit and the incidence of treatment-related adverse events.

Results: In total, 1067 patients from 46 skin cancer centers were included. Most of the patients (63%) had received immune checkpoint inhibitors (ICI) as last-line therapy, 22% targeted therapies (TT) and 12% chemotherapy (CTX). Comparing last-line ICI and TT, patients with TT were significantly more likely to benefit from treatment and had significantly fewer and milder treatment-related AE than patients with ICI. Even though two thirds of patients had received ICI as a last-line therapy, the majority of these patients (61%) had stopped therapy within the last 30 days of life, whereas the majority of patients with TT (66%) still continued their treatment to the end of life. We found markedly fewer patients with initiation of ICI within 30 days before their death (19%) compared to a historic cohort including patients who died in 2016 or 2017 (39%).

Conclusion: Treatment approaches near the end of life have markedly changed in skin cancer centers in Germany over recent years, with ICI prescribed less frequently in the end-of-life phase. In contrast, TT are frequently administered, even within the last 30 days of life. It should also be considered that discontinuation of TT can result in rapid tumor progression. Due to the oral administration and a low rate of severe toxicity, TT appear to be a suitable treatment option, even in the end-of-life situation of melanoma patients.

Introduction

The introduction of immune checkpoint inhibitors (ICI) and targeted therapies (TT) has drastically improved treatment options and survival rates in advanced melanoma (1–3). However, these therapies can cause serious adverse events (AE)and their use as last-line treatment has not been evaluated in prospective trials, highlighting the need for careful risk-benefit assessment of their use in the end of life. There are only a few publications on this topic and benefit assessment is rarely reported (4–7).

In 2021, the Supportive Care Committee of the Dermatologic Cooperative Oncology Group (DeCOG) published a study evaluating systemic therapies in 193 patients with advanced melanoma from 4 skin cancer centers who had died in 2016 or 2017 and were still receiving oncological systemic therapy within the last 3 months of their life (8). Most of the patients (57%) had received ICI, about one third of these patients developed severe irAE and only a small proportion (15%) benefited from last-line ICI. TT as last-line treatment resulted in a significant higher proportion of patients with benefit and fewer severe AE. Here, we assessed current trends in end of life treatment based on data from a nationwide prospective registry of patients with metastatic melanoma in Germany (ADOReg).

Methods

Patients with metastatic melanoma who died between January 1, 2018 and October 31, 2022 were identified from the prospective multicenter skin cancer registry ADOReg of the German Dermatologic Cooperative Oncology Group (DeCOG). The ADOReg was approved by the Medical Ethics Committee of the University Duisburg-Essen (14-5921-BO), and written informed consent for participation was obtained from all patients. Study endpoints were the percentage of patients who had been on systemic therapy within the last three months of life, timepoint of initiation of the last-line therapy, overall survival, treatment benefit and the incidence of treatment-related adverse events. Furthermore, the total number of systemic non-adjuvant therapies was assessed. Benefit of last-line therapy was assessed according to the best response as documented in ADOReg. If the documented response was stable disease, mixed, complete or partial response, the patients were judged to have benefited for the treatment. Patients with progressive disease were classified as not benefiting. Patients with no available response evaluation were classified as “unknown”. Toxicity was classified according to the classification of Common Terminology Criteria for Adverse Event (CTCAE) version 5. The baseline performance status was classified according to the Eastern Cooperative Oncology Group (ECOG) performance status scale and refers to the time of initiation of last-line therapy. ECOG 0 describes patients who are fully active without restriction, ECOG 4 stands for completely disabled patients totally confined to bed. The two most common last-line systemic therapies, ICI and TT, were statistically tested for potential significant differences using chi-squared tests. When the expected cell frequency of at least one cell was less than five, Fisher’s exact test was used. Medians were compared with the median test. Overall survival (OS) was calculated as time from start of last-line systemic therapy until death. Kaplan-Meier estimates were used for OS calculation, differences between groups were assessed by two-sided log-rank tests. P values <0.05 were considered statistically significant. Statistical analyses were performed with IBM SPSS Statistics V.28. Survival curves were made with STATA/IC version 15.1.

Results

Patient cohort

In total, 1067 patients were identified from 46 different skin cancer centers. The majority (63%) had received ICI as last-line therapy, 22% had received TT and 12% chemotherapy (CTX). More than half of all patients with ICI (52%) had combined CTLA-4 and PD-1 antibodies and most patients with targeted therapy (89%) had a combination of BRAF- and MEK inhibitors (Table 1). About three quarters of the patients (74%) underwent systemic therapy within 90 days of death, approximately half of the patients within 30 days of death. The last line of therapy had been started within the last 30 days before death in 13% of patients; within 7 days before death in 2%. The median time from treatment initiation to death was 127 days, interquartile range (IQR) 57 – 279 days. Almost one third of the patients had brain metastases and in half of the patients lactate dehydrogenase (LDH) was elevated baseline to last treatment initiation. In one third, baseline performance status according to the Eastern Cooperative Oncology Group (ECOG) was ≥1, in 40% of the patients ECOG was unknown. Approximately 40% of the patients had received three or more systemic therapies before death. This percentage was highest in patients with CTX as the last-line treatment (69%), followed by TT (50%) and ICI (29%). Among all patients with BRAF V600 mutation, 52% had TT as last-line therapy. About 44% of the patients with last-line TT had already been treated with TT at an earlier time point, i.e. they received TT as a re-challenge. The proportion of patients with benefit from last-line therapy was highest in patients with TT, followed by ICI and CTX (Supplementary Table S1). OS was significantly worse for patients with CTX as the last-line therapy (p=0.004) (Figure 1).

Table 1

Table 1. Patient characteristics (n=1067).

Figure 1

Figure 1. Overall survival since treatment initiation of last-line systemic therapy. ICI, immune checkpoint inhibitors; TT, Targeted therapies; CTX, Chemotherapy.

Comparison between ICI and TT

Even though the majority (63%) of patients had received ICI as last-line therapy within their last 3 months of life, almost two thirds (61%) of these patients with ICI stopped therapy within the last 30 days of life. In contrast, the majority of patients (66%) with TT still continued TT within the last days of life (p<0.001) (Table 2). The percentage of patients with treatment initiation within the last 30 days of life was similar in both groups, i.e., 13% of patients with ICI and 12% of patients with TT.

Table 2

Table 2. Immune checkpoint inhibitor versus targeted therapy as last-line treatment.

Considering the number of systemic therapies that had been applied before death, patients with TT had had significant more treatment lines, half of them ≥ 3. Patients with ICI had received in more than 40% of the cases only one systemic therapy before death (p<0.001). LDH baseline was normal in one third of patients with ICI and in 21% of patients with TT (p<0.001). The proportion of patients who benefited from last-line treatment was significantly higher in the TT group (37%) compared to the ICI group (25%). Though, it has to be considered that the benefit had not been documented in about one third of patients of both groups. When only patients with known benefit status are considered, the difference was even greater: 51% of patients with TT benefited from last-line treatment compared to 36% of patients with ICI. Regarding treatment-related AEs, 33% of patients with ICI and 22% of patients with TT had toxicity due to last-line therapy, respectively (Figure 2; Table 3). The percentage of CTCAE toxicity grade 3 or 4 was double for ICI (14%) compared to the TT group (7%). Regarding OS since treatment initiation of last-line therapy, there was no significant difference between the ICI and TT group (p=0.791) (Figure 1).

Figure 2

Figure 2. Treatment benefit and toxicity of last-line ICI (green, left part) and TT (blue, right part).

Table 3

Table 3. Treatment-related adverse events with immune checkpoint inhibitor and targeted therapy as last-line treatment.

Discussion

Patients with TT were not only significantly more likely to benefit from therapy, they also suffered significantly fewer treatment-related AE compared to patients who received ICI as the last line therapy. These results confirm the data from our previously published study that included a notably smaller cohort (6). At that time, it was assumed that the large number of patients that had commenced the newly approved ICI therapy may have reflected unrealistic expectations of treatment response (8). In the cohort of patients who had died in 2016-2017, 85% of the patients with last-line ICI had ECOG performance status ≥1. In the present study only 47% of patients with known performance status had ECOG ≥1. Similarly, the proportion of patients with ICI and normal LDH values was significantly lower (26%) in the historical cohort compared to the current cohort (42%). In both cohorts, the ECOG and LDH values of the TT group were significantly worse compared to the respective ICI cohort and the proportion of patients who benefited from last-line TT was significantly higher. This further supports the approach of re-challenge with BRAF and MEK inhibitors in melanoma (9). It should also be mentioned at this point, that TT are an oral medication that can be administered by patients at home, whereas ICI have to be administered intravenously at medical centers. In case of toxicity, treatment-related AE usually cease with treatment discontinuation and hospitalization is only required in rare cases. It should also be considered that if TT are discontinued because of disease progression, even faster metastatic growth is commonly observed. Due to the oral administration and a low rate of high-grade toxicity, TT appear to be a suitable treatment option, even at the end of life. In view to the limited prognosis in patients with re-challenge of TT this is an important aspect to be considered. Patients with CTX had worst survival and lowest benefit rate. These results confirm the limited efficacy of CTX in patients with advanced melanoma (10). Considering patients’ wishes regarding end of life situation, most of them wish to die at home. Therefore, physicians should honestly discuss potential benefit and expected effort/toxicity of treatments near end of life. CTX is in most cases associated with hospitalization and significant toxicity, so there is a high risk that CTX will do more harm than good to patients at the end of life (11–13).

We found a significantly lower percentage of patients for whom ICI was initiated within 30 days of death (19%) compared to the historic cohort (39%). It is evident that a learning process has taken place here, which has probably led to a more realistic assessment of risk and benefit at the end of life. This is also supported by survival analyses. In the historic cohort, OS since treatment initiation of last-line therapy was significantly worse in patients with last-line ICI compared to TT. In the present study, which reflects the approach of the centers in the period well after approval of ICI, there is no difference, which is probably due to the fact that ICI treatment was no longer initiated in patients approaching the end of life.

In a retrospective cohort study of a US national clinical database of patients with metastatic melanoma and other cancer types between 2016 and 2019, it was observed that the number of patients with initiation of ICI within 1 months before death increased much more than other therapies decreased, thus, ICI were added as an additional therapy at the end of life. The authors concluded that there was an unrealistic hope in ICI even within the last days of life. They found that academic centers and centers with high numbers of patients were more reluctant to initiate ICI within 30 days before death. The authors speculated that these centers might manage severe irAE more often and prescribe ICI with greater caution to “borderline” candidates, i.e., with reduced ECOG near end of life (6).

Furthermore, it is well known that the availability of new therapies is usually accompanied by a simultaneous increase in their prescription. However, the transfer of study data to a real-world setting is challenging and should not simply be adopted without reflection. With regard to ICI, this phenomenon was particularly pronounced, perhaps because patients and physicians tended to underestimate potential toxicities and overestimate potential benefits of ICI. It has been shown that the use of anti-cancer therapies near end of life in patients with advanced melanoma who died between 2013 and 2017 has increased significantly since ICI had been approved (14).

In the present evaluation of a large real-world cohort we found that the percentage of patients with treatment initiation within the last 30 days of death has significantly decreased over time, which may reflect an improved ability of physicians to assess prognosis more realistically and to consider potential risks of ICI more carefully. Treatment approaches near end of life have apparently changed over recent years in dermato-oncology centers in Germany, which can certainly be attributed to an increase in knowledge in the care for patients with advanced melanoma at the end of their lives.

A more realistic assessment of available treatment options and open and honest conversations with patients and their families will enable them to plan the last phase of their lives according to their wishes and needs at the end of life (15, 16). It is important to recognize that there is a fine line between providing effective treatments that have a positive impact on patients’ lives and overtreatment causing more harm than good. Early integration of palliative care rather than aggressive systemic therapy has been shown to improve quality of life and even prolong survival, as has been shown in lung cancer (17). A recent publication addressed factors that contribute to overtreatment of cancer patients at the end of life. The authors encourage open, unbiased conversations, early implementation of palliative care and considering patient’s individual goals in order to avoid overtreatment as far as possible (18).

There are some limitations of our study. First, the information on benefit was not always documented in the ADOReg registry. The proportion of patients with missing data on benefit was about one third in all treatment categories (ICI, TT and CTX). When calculating the percentage of patients with benefit, we only included patients with known data. The lack of response assessment is likely due to a deteriorating performance status of this advanced cohort and the increasing inability to undergo imaging procedures. The percentage of patients with toxicity in general and specifically of grade 3 or 4 was low. This might be due to insufficient documentation in the medical files, which are reviewed by the documentaries of the skin cancer centers. However, there is no reason to suggest this biased the results in terms of TT or IT as it applies to all treatment types and should not detract from the conclusion that ICI patients had more often and more severe toxicity compared to TT. The strength of this study is the high number of patients and the accurate documentation of data on treatment initiation, death and patients’ treatments before death. The results of our data are important because they reflect the real-world situation of melanoma patients near end of life in more than 40 different skin cancer centers in a very large cohort. National registries such as the ADOReg are extremely important to obtain such data.

We believe that our study makes a significant contribution to the care of patients with metastatic melanoma at the end of life. Treatment approaches have obviously changed over years in Germany, with a decrease of the use of ICI at the end of life. In contrast, TT are still of high relevance, even within the last 30 days of life. Due to the oral administration and a low rate of high-grade toxicity, TT appear to be a suitable palliative treatment option, even at the end of life.

Data availability statement

The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.

Ethics statement

The studies involving humans were approved by Medical Ethics Committee of the University Duisburg-Essen (14-5921-BO), Essen University Hospital, West German Cancer Center, University of Duisburg-Essen and the German Cancer Consortium (DKTK), partner site Essen/Düsseldorf, Germany. The studies were conducted in accordance with the local legislation and institutional requirements. The participants provided their written informed consent to participate in this study.

Author contributions

AF: Conceptualization, Data curation, Formal analysis, Methodology, Visualization, Writing – original draft, Writing – review & editing. KK: Writing – original draft, Writing – review & editing. MGs: Writing – original draft, Writing – review & editing. EL: Writing – original draft, Writing – review & editing. CW: Writing – original draft, Writing – review & editing. FraM: Writing – original draft, Writing – review & editing. K-MT: Writing – original draft, Writing – review & editing. RW: Writing – original draft, Writing – review & editing. DG: Writing – original draft, Writing – review & editing. MGa: Writing – original draft, Writing – review & editing. MSa: Writing – original draft, Writing – review & editing. MSc: Writing – original draft, Writing – review & editing. MR: Visualization, Writing – original draft, Writing – review & editing. IK: Writing – original draft, Writing – review & editing. AG: Writing – original draft, Writing – review & editing. PM: Writing – original draft, Writing – review & editing. FriM: Writing – original draft, Writing – review & editing. IV: Writing – original draft, Writing – review & editing. RH: Writing – original draft, Writing – review & editing. JUt: Writing – original draft, Writing – review & editing. CP: Writing – original draft, Writing – review & editing. JUl: Writing – original draft, Writing – review & editing. PT: Writing – original draft, Writing – review & editing. MK: Writing – original draft, Writing – review & editing. SH: Writing – original draft, Writing – review & editing. UL: Writing – original draft, Writing – review & editing. SU: Writing – original draft, Writing – review & editing. MW: Writing – original draft, Writing – review & editing. CB: Writing – original draft, Writing – review & editing. RG: Writing – original draft, Writing – review & editing. DS: Writing – original draft, Writing – review & editing. LN: Data curation, Formal analysis, Validation, Writing – original draft, Writing – review & editing. CL: Supervision, Writing – original draft, Writing – review & editing.

Funding

The author(s) declare that no financial support was received for the research, authorship, and/or publication of this article.

Conflict of interest

AF: served as a consultant to Novartis, MSD, BMS, Pierre-Fabre and Immunocore; received travel support from Novartis, BMS, Pierre-Fabre, MSD, received speaker fees from Novartis, Delcath, BMS and MSD and reports institutional research grants from BMS Stiftung Immunonkologie. KK: Honoraria: BMS, MSD, Novartis, Sanofi-Aventis, Immunocore, Philogen, Consulting or Advisory Role: BMS, MSD, Pierre Fabre, Philogen, Sun Pharma, Speakers’ Bureau: No Relationships to Disclose, Research Funding: Novartis,Travel, Accommodations, Expenses: BMS, MSD, Novartis, Roche, Pierre Fabre,Sun Pharma. MGs Honoraria for lectures/advisory boards BristolMyers Squibb, MerckSharpDohme, Merck-Serono, Almirall Hermal, Sun Pharma, Delcath, Sanofi/Regeneron and travel support from Almirall Hermal and Pierre Fabre, outside the submitted work. EL Honoraria for lectures/advisory boards BristolMyers Squibb, Novartis, Sun Pharma outside the submitted work. FraM served as consultant and/or has received honoraria from Novartis, Bristol-Myers Squibb, Merck Sharp & Dohme, Pierre Fabre, Sanofi Genzyme, Sun Pharma and travel support from Novartis, Sun Pharma, Pierre Fabre and Merck Sharp & Dohme, outside the submitted work. K-MT received honoraria for lectures or advisory boards from Bristol Myers Squibb, MSD, Pierre Fabre, Novartis, Roche, Immunocore, Sanofi, Sun Pharma, Amgen, LEO Pharma, Galderma, Almirall, Candela and Lilly. DG served as a consultant to Novartis, Pierre-Fabre, Bristol Myers Squibb, MSD Sharp & Dohme, Sun Pharma, Sanofi, Immunocore and Janssen; received travel and conference support from Pierre-Fabre, Kyowa Kirin and Sun Pharma, received speaker fees from Janssen and Sun Pharma. MGa reports honoraria and travel support from Amgen, Bristol Myers Squibb, MSD, Novartis, Pierre Fabre, Roche, and Sanofi. MSc Advisory boards of Bristol-Myers Squibb, Novartis, MSD, Pierre Fabre, Kyowa Kirin, Immunocore, and Sanofi-Genzyme. Travel accommodation and expenses by Novartis, Pierre Fabre, and Sun Pharma. MR received a funding as part of the Clinician Scientists Program of the University of Tübingen (application no. 523-0-0) and travel support from Almirall Hermal and Pierre Fabre, outside the submitted work. IK is employee of Helios Klinikum Erfurt GmbH. AG served as consultant and/or has received honoraria or travel costs from Allmiral, Amgen, Bristol-Myers Squibb, Immunocore, MSD Sharp & Dohme; Novartis, Pierre Fabre Pharmaceuticals, Pfizer, Roche and Sanofi Genzyme, outside the submitted work. PM reports institutional grants from Bristol Myers Squibb, MSD, and Novartis; personal fees and honoraria from Amgen, Bristol Myers Squibb, GSK, MSD, Merck Serono, Novartis, Pierre Fabre, Roche, Sanofi, and Sun Pharma; and travel support from Bristol Myers Squibb. PM participated on a data safety monitoring or advisory board from Almirall Hermal, Amgen, Beiersdorf, Bristol Myers Squibb, MSD, Merck Serono, Novartis, Pierre Fabre, Roche, Sanofi, and Sun Pharma, and received travel support from Bristol Myers Squibb and Sun Pharma. FriM reports consulting fees and honoraria and participation on a drug safety monitoring or advisory board for Bristol Myers Squibb, MSD, Novartis, Pierre Fabre, Roche, and Sanofi, and support for attending meetings or travel grants from Bristol Myers Squibb, MSD, Pierre Fabre, and Sanofi. IV received honoraria for lectures or advisory boards from Bristol Myers Squibb, MSD, Pierre Fabre, Novartis, Regeneron, Sanofi and Stemline. RH is employee of Helios Klinikum Erfurt GmbH. JUt is on the advisory board or has received honoraria and travel support from Amgen, Bristol Myers Squibb, GSK, Immunocore, LeoPharma, Merck Sharp and Dohme, Novartis, Pierre Fabre, Rheacell, Roche, Sanofi outside the submitted work. CP served as consultant and/or has received honoraria from Bristol-Myers Squibb, Merck Sharp & Dohme, Novartis, Sanofi, Sunpharma, Pierre Fabre, AbbVie, Kyona Kirin and Amgen and received travel support from Amgen, Merck Sharp & Dohme , Bristol-Myers Squibb , Pierre Fabre, Sunpharma and Novartis, outside the submitted work. JUl served as a consultant to BMS, Sun Pharma, and Regeneron; received speaker fees from BMS, MSD, Novartis, Pierre-Fabre, Sanofi, Regeneron and Sun Pharma. PT served as consultant and/or received honoraria form Almirall, Bristol Myers Squibb, Biofrontera, Kyowa Kirin, L’Oréal, Merck Sharp & Dohme, Novartis, Pierre-Fabre, Sanofi, 4SC, and travel support from Bristol Myers Squibb outside the submitted work. MK Honoraria for lectures/advisory boards, studies: BMS, Sunpharma, MSD, Novartis, Immunocore, Regeneron, Pierre Fabre. SH Honoraria for lectures/advisory boards BristolMyers Squibb, MerckSharpDohme, Novartis, Pierre-Fabre, Sun Pharma, Immunocore, Sanofi/Regeneron UL served as a consultant to Novartis, MSD, Sun Pharma, Sanofi and Regeneron; received travel support from Pierre-Fabre and Sun Pharma, received speaker fees from Sanofi, Regeneron and Sun Pharma, and reports institutional research grants from MSD. SU declares research support from Bristol Myers Squibb and Merck Serono; speakers and advisory board honoraria from Bristol Myers Squibb, Merck Sharp & Dohme, Merck Serono, and Novartis; and meeting and travel support from Almirall, Bristol-Myers Squibb, IGEA Clinical Biophysics, Merck Sharp & Dohme, Novartis, Pierre Fabre, and Sun Pharma. CB Honoraria for lectures/advisory boards from Bristol Myers Squibb, Merck Sharp Dohme, Novartis, Almirall Hermal, Leo Pharma, Pierre Fabre, InflaRx, Immunocore, Delcath, Sanofi, Regeneron; RG: Honoraria for lectures/advisory boards BristolMyers Squibb, MerckSharpDohme, Novartis, Merck-Serono, Amgen, Almirall Hermal, Pierre-Fabre, Sun Pharma, Immunocore, 4SC, Delcath, Sanofi/Regeneron; Meeting support SUN Pharma, Boehringer Ingelheim, PierreFabre; Research support (to institution) Novartis, Sanofi/Regeneron, Merck Serono, Amgen, SUN Pharma, KyowaKirin, Almirall Hermal. DS a member of the advisory board, consultant or received speakers´ honoraria from: Astra Zeneca, BMS, CureVac, Daiichi Sankyo, Erasca, Haystack, Immatics, Immunocore, InFlarX, Lapcorp, Merck-Serono, MSD, Neracare, Novartis, Novogenix, PamGene, Philogen, Pierre Fabre, Pfizer, Regeneron, Replimune, Sanofi, Seagen, Sun Pharma, UltraVacs; research funding from BMS, Roche, MSD, Amgen & Novartis. CL Advisory Board: BMS, MSD, Merck, Roche, Immunocore, Novartis, Pierre Fabre, Sanofi, Sun Pharma, Almirall Hermal, Kyowa Kirin, Biontech. Speakers fee: BMS, MSD, Merck, Roche, Immunocore, Novartis, Pierre Fabre, Sanofi, Sun Pharma, Almirall Hermal, Kyowa Kirin, Biontech. Travel reimbursement: BMS, MSD, Merck, Roche, Immunocore, Novartis, Pierre Fabre, Sanofi, Sun Pharma, Almirall Hermal, Kyowa Kirin, Biontech.

The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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Supplementary material

The Supplementary Material for this article can be found online at: https://www.frontiersin.org/articles/10.3389/fimmu.2025.1509886/full#supplementary-material

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