Impact of Acute and Chronic Adverse Events on Quality of Life in Cutaneous Melanoma

Background/Objectives: The advent of immune checkpoint inhibitors (ICIs) and targeted therapies has revolutionized advanced cutaneous melanoma care, shifting it from an acutely fatal illness to a chronic, manageable condition. While extending survival, these modern therapies introduce a new spectrum of persistent immune-related adverse events (irAEs) and long-term toxicities. This study aims to explore the “Toxicity-HRQoL Paradox” to comprehensively evaluate the true price of survival across the melanoma treatment continuum. Methods: This narrative review, based on a systematic database search, synthesizes quantitative patient-reported outcomes, health-related quality of life (HRQoL) trajectories, and health-economic data. It evaluates the impact of surgical, regional, and modern systemic therapies utilizing data derived from validated instruments, including the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30), EuroQol 5 Dimensions (EQ-5D), Functional Assessment of Cancer Therapy-Melanoma (FACT-M), and comprehensive score for financial toxicity (COST). Results: Historically, extensive locoregional surgeries and high-dose interferons caused profound, debilitating drops in physical and overall QoL. Today, modern systemic therapies are associated with high rates of severe (Grade ≥ 3) acute toxicities and irreversible chronic conditions, such as permanent endocrinopathies. Despite this, global HRQoL frequently remains stable or even improves. This “toxicity-HRQoL paradox” occurs because the profound psychological relief of durable disease control effectively offsets the physical symptom burden. Furthermore, neoadjuvant ICI approaches demonstrate superior long-term HRQoL by enabling tailored surgical de-escalation. Ultimately, extended survivorship unmasks hidden burdens, revealing high prevalences of fear of cancer recurrence (FCR) (81–86%) and substantial financial toxicity. Conclusions: Despite the severe physical toxicities of modern melanoma treatments, the psychological benefit of survival largely preserves overall HRQoL. However, optimizing the modern survivorship experience requires the widespread adoption of melanoma-specific HRQoL tools and proactive, multidisciplinary care models to manage chronic toxicities, psychosocial distress, and financial burdens.