# Investigating Chronic Toxicity, Diet, Patient-Reported Outcomes and the Microbiome in Immunotherapy-Treated Metastatic Melanoma Survivors: A New Frontier

## TL;DR

This study explores how long-term survivors of melanoma treated with immunotherapy experience chronic side effects, and how diet and gut bacteria might be connected.

## Contribution

The study introduces a new focus on chronic toxicity and microbiome features in long-term melanoma survivors treated with immunotherapy.

## Key findings

- 60% of patients experienced chronic toxicity, with distinct gut microbiome differences observed.
- Higher fruit and vegetable intake was linked to lower anxiety symptoms.
- Added sugar consumption correlated with symptom severity, including pain and fatigue.

## Abstract

Background/Objectives: Immune checkpoint blockade (ICB) therapies have significantly improved outcomes in metastatic melanoma. However, immune-related adverse events (irAEs) and persistent chronic toxicities (CTs) among this emerging survivor population likely influence different facets of quality of life. This study characterized CT, patient-reported outcomes (PROs), diet, physical activity and gut microbiome features in a cohort of long-term survivors with a history of ICB-treated metastatic melanoma. Methods: Forty-eight patients with a history of metastatic melanoma who initiated ICB treatment at least 3 years earlier and were not currently on treatment were prospectively enrolled from a melanoma survivorship clinic. Participants completed screening questionnaires for depression, anxiety, diet and physical activity. The gut microbiome was characterized via metagenomic sequencing in a subsample (n = 39). Patients’ clinicopathological characteristics and experience of irAEs (during treatment) and CT (persisting >6 months after completion of therapy) were extracted retrospectively from the medical record. Results: In the overall cohort, 60% were experiencing CT, while 16% and 20% reported clinically relevant levels of depression and anxiety symptoms, respectively. We observed significant differences in overall gut microbiome composition between survivors with and without CT (p = 0.02). Consumption of fruit and vegetables was inversely associated with anxiety (ρ = 0.3, p = 0.038). Added sugar consumption was correlated with the severity of experienced symptoms (ρ = 0.4, p = 0.003), with pronounced associations across the spectrum of symptoms, including pain, fatigue and shortness of breath (p < 0.05). Conclusions: These results suggest that CT is experienced by a substantial proportion of ICB-treated metastatic melanoma survivors. Patients experiencing CT also showed distinct microbiome features. However, additional research in prospective settings is needed to confirm these hypotheses.