Dermatology: Practical and Conceptual Original Article | Dermatol Pract Concept. 2024;14(3):e2024118 1 The Impact of Immune Checkpoint Inhibitors- Induced Skin Toxicity on Patients Quality of Life and the Role of Dermatologic Intervention Christina Kemanetzi1, Konstantinos Lallas2, Elizavet Lazaridou1, Chrysoula Papageorgiou1, Aimilios Lallas3, Alexandros Stratigos4, Eleni Timotheadou2, George Lazaridis2, Dimitrios Dionysopoulos2, Kalliopi Kalaitzi5, Antonios Tsimpidakis4, Myrto Trakatelli1, Aikaterini Patsatsi1, Vasiliki Nikolao4, Zoe Apalla1 1 Second Department of Dermatology, School of Health Sciences, Aristotle University of Thessaloniki, Papageorgiou General Hospital, Thessaloniki, Greece 2 Oncology Department, School of Health Sciences, Aristotle University of Thessaloniki, Papageorgiou General Hospital, Thessaloniki, Greece 3 First Department of Dermatology, School of Health Sciences, Aristotle University of Thessaloniki, Thessaloniki, Greece 4 First Department of Dermatology-Venereology, National and Kapodistrian University of Athens, School of Medicine, Andreas Sygros Hospital, Athens, Greece 5 Attikon Hospital, Athens Medical School, Athens, Greece Key words: checkpoint inhibitors, skin toxicity, skin rash, quality of life, patient reported outcomes Citation: Kemanetzi C, Lallas K, Lazaridou E, et al.The Impact of Immune Checkpoint Inhibitors-Induced Skin Toxicity on Patients Quality of Life and the Role of Dermatologic Intervention. Dermatol Pract Concept. 2024;14(3):e2024118. DOI: https://doi.org/10.5826/ dpc.1403a118 Accepted: January 14, 2024; Published: July 2024 Copyright: ©2024 Kemanetzi et al. This is an open-access article distributed under the terms of the Creative Commons Attribution- NonCommercial License (BY-NC-4.0), https://creativecommons.org/licenses/by-nc/4.0/, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original authors and source are credited. Funding: None. Competing Interests: None. Authorship: All authors have contributed significantly to this publication. Corresponding Author: Zoe Apalla, PhD, Associate Professor of Dermatology, Aristotle University of Thessaloniki. Address: Anatolis 5, 55535, Thessaloniki, Greece, Tel. +306972916729, Email: zoimd@yahoo.gr Introduction: Data regarding quality of life (QoL) of oncologic patients experiencing dermatologic immune-related adverse events (dirAEs) and their course after dermatologic intervention are scarce. Objectives: To assess the impact of dirAEs on patients QoL and to investigate the correlation between dermatologic and oncologic indexes used for estimating QoL. Methods: We enrolled oncologic patients with dirAEs managed in two supportive onco- dermatology outpatient clinics in Greece. Patient-reported outcomes included DLQI, EORTC-QLQ-C30 and Numerical Rating Scale for pruritus (pNRS). ABSTRACT 2 Original Article | Dermatol Pract Concept. 2024;14(3):e2024118 Introduction The introduction of immune checkpoint inhibitors (ICIs) (CTLA-4, PD-1, PD-L1) in the therapeutic armamentarium of oncologists wasa major breakthrough in cancer therapy. Due to their unique mechanism, ICIs induce a new spectrum of adverse events that are described with the term immune related adverse events (irAEs) and practically represent a class effect of these drugs. Among them, dermatologic irAEs (dirAEs) are the most common, affecting up to 50% of treated patients [1-5]. DirAEs include eczematous, lichenoid and psoriasiform- rashes, pruritus, vitiligo-like rash, auto-immune bullous diseases-like rash, as well as other less common skin tox- icities [2,3,5-7]. Importantly, cumulative data suggest that development of certain skin toxicities linked to a better on- cologic outcome, as indicated by the longer progression-free and overall survival in these patients [8-10]. The Quality-of-Life (QoL) Index is a multidimensional concept that describes the impact of a person health status on QoL. It involves many aspects of life, including physi- cal and mental health [11,12]. From the limited available literature data, it appears that skin toxicities triggered by ICIs have a significant impact on patients QoL. The use of tools evaluating QoL and the collection of patient-reported outcomes (PROs) before and after therapeutic interventions, is of paramount importance in modern medicine. PROs re- flect patients needs and their perspective regarding treatment outcome and should be considered in treatment decision- making [13]. The Dermatology Life Quality Index (DLQI) is a 10-question questionnaire used to gauge the impact of skin diseases on the patients QoL. Each question receives a score from 0 (“not at all”) to 3 (“very much”). The sum gives the total score that ranges from 0-30. A score over 10 indicates that the patient QoL is being severely affected by the skin disease [14-15]. The numerical rating scale for pruritus (pNRS) is a widely used ten-point numerical scale, in which 0 represents “no” itch and 10 represents “maximum” itch. The EORTC-QLQ-C30 is a specialized questionnaire, developed in 1988 to capture the QoL of oncologic pa- tients. It includes 9 sections: 5 functional sections (physical condition, posture, perceptual ability, emotional and social functioning), 3 symptom-related sections (fatigue, pain and nausea) and 1 section regarding the patient general health status (GHS) [11,12]. Scores range from 0 to 100, with a 10-point score shift corresponding to a clinically meaningful change [16]. A high score in functional scales suggests a high/ healthy level of functioning, which translates to a higher overall health status/QoL. In contrast, a higher score on a physical symptom scales indicates a higher level of prob- lems [17]. Objectives In this study we aimed to record the impact of dirAEs on patient QoL, using DLQI, pNRS and EORTC-QLQ-C30 and the modification of these scores after therapeutic inter- ventions by specialized dermatologists. We also attempted to correlate baseline patients and toxicity characteristics with QoL. Furthermore, we tested the correlation between the dermatology QoL index and EORTC-QLQ-C30, in order to clarify whether the latter can adequately capture the QoL impairment induced by skin toxicity. Methods The study was conducted in two supportive onco- dermatology outpatient clinics in Greece. Oncologic patients who developed dirAEs from July 2020 to July 2022 and were referred for dermatologic consultation were enrolled for the aims of the study. The study received approval from the Institutional Ethical Committee (6296/01-Jul-2020) Results: Overall, 110 patients were enrolled in the study. Mean (standard deviation) DLQI and pNRS scores were 15.54 (5.44) and 7.25 (2.95), correspondingly, while functional, symptom and summary scores of EORTC-C30 were 79.17 (2.11), 17.66 (3.60) and 80.67 (3.08), respectively. After therapeu- tic interventions, there was a statistically significant decrease in DLQI scores after first intervention compared to baseline, and second intervention compared to first (mean decrease 4.38 (2.91), P < 0.001 and 5.16 (3.99), P < 0.001, respectively). DLQI showed no correlation with global health status/QoLs (rho 0.01, P = 0.90) of EORTC-C30. Conclusions: DirAEs negatively affect QoL. Dermatologic intervention improves patients QoL, fa- cilitating an unimpaired oncologic treatment. Poor correlation between DLQI and EORTC-QLQ-30 highlights the need for adapted QoL measurement tools in the context of immune checkpoint inhibi- tors treatment. Original Article | Dermatol Pract Concept. 2024;14(3):e2024118 3 and it was conducted in accordance with the provisions of Helsinki Declaration and good clinical practice guidelines. All participants provided written informed consent before undergoing any procedure related to the study. Inclusion cri- teria were age >18 years and the appearance of at least one dirAEs due to ICIs. Exclusion criteria were co-morbidities and co-medications that could result in development of skin rashes similar to dirAEs, as well as individuals who did not have adequate level of Greek language, or were mentally and physically unable to complete the questionnaires. The patients first visit included the clinical assessment of the skin rash, the evaluation of its severity based on the CT- CAE v4.0 criteria, the completion of the DLQI, pNRS and EORTC-QLQ-C30 questionnaires and the administration of treatment according to standard clinical practice [18,19]. IrAEs, including dirAEs, were recorded.during follow-up vis- its, scheduled at 4 and 12 weeks from baseline. During the follow-up visits, the severity of irAEs based on CTCAE was evaluated and EORTC-QLQ-C30, DLQI, and pNRS were collected. Additional recorded data included the evolution of the underlying neoplasm and the impact of the dermatologic adverse event on the oncologic treatment. Topography of the rash was documented with the use of digital imaging at base- line and follow-up visits. Statistics A descriptive analysis with mean and standard deviation for continuous variables and frequencies for categorical was conducted. Following normality considerations, Mann– Whitney t-test (or ANOVA Kruskal–Wallis) and Wilcoxon rank test were used for comparisons in unpaired and paired variables, respectively. In order to investigate possible cor- relation among QoLs scores, Spearman rho was preferred. Also, for DLQI and pNRS, a change in score ≥ 4 was con- sidered as clinically significant, while for global health and Summary score the change was set ≥10.20,21 Moreover, linear mixed models were used to evaluate the change of QoLs af- ter therapeutic interventions and to compare change in score between patients with and without pruritus. All statistical tests were two-sided, P < 0.05 was considered significant and the analysis was conducted with the Statistical Package for Social Sciences statistical software (version 28.0, IBM SPSS Statistics for Windows). Results Demographic and Baseline Characteristics Overall, 110 patients with a mean age of 67 years (range 37-86) who received ICIs for various oncologic indications were included in the analysis. The most common type of pri- mary cancer was NSCLC (53 patients, 48.2%) followed by melanoma (25 patients, 22.7%). Most of the patients were treated with anti-PD1 (93 patients, 84.5%). The epidemio- logical and clinical characteristics of the patients at baseline can be found in the supplement table. The most prevalent dirAE was psoriasis-like rash (35 out of 110, 31.8%), followed by eczema-like rash (22 patients, 20%) and pruritus (15 patients, 13.6%). Fifteen individuals experienced two different types of dirAE. The most common dirAE in the latter group was vitiligo (6 out 15 patients, 5.5%). Responsiveness Analysis At baseline, mean (standard deviation, SD) DLQI score was 15.54 (5.44), pNRS was 7.25 (2.95), while functional, symp- tom and summary scores of EORTC-C30 were 79.17 (2.11), 17.66 (3.60) and 80.67 (3.08), respectively. After therapeu- tic interventions, there was a statistically significant decrease in DLQI scores between the first intervention compared to baseline, and between the second intervention compared to th efirst [mean (SD) decrease 4.38 (2.91), P < 0.001 and 5.16 (3.99), P < 0.001, respectively]. The same statistically sig- nificant difference was seen for pNRS scores after each inter- vention (Table I). Regarding Summary score of EORTC-C30, a significant increase in mean scores was detected after the first (mean increase 1.34 (2.64), P < 0.001) and the second intervention (mean increase 0.96 (2.26), P < 0.001), but the same significant association was not detected for functional Table 1. Mean of main QoLs scores and their change after each intervention. Baseline 1st intervention P 2nd intervention P DLQI 15.54 (5.44) 11.15 (6.07) P<0.001 5.99 (4.70) P<0.001 Global health-QoL 59.16 (13.4) 65.90 (10.1) P<0.001 66.4 (9.71) P=0.47 pNRS 7.25 (2.95) 5.25 (3.11) P<0.001 3.47 (2.79) P<0.001 Functional score 79.17 (2.11) 79.04 (1.85) P=0.46 79.07 (1.95) P=0.98 Symptom score 17.66 (3.60) 16.1 (3.56) P<0.001 14.6 (3.99) P<0.001 EORTC-QLQ-C30 Summary score 80.67 (3.08 82.01 (2.33) P<0.001 83.0 (2.59) P<0.001 DLQI = Dermatology Quality of Life Index; pNRS = numerical rating scale for pruritus; QoL = Quality-of-Life. 4 Original Article | Dermatol Pract Concept. 2024;14(3):e2024118 further increased after the second intervention,as compared to first. On the other hand, considering the global QoL score, a significant change was detected in 19 patients (17.3%) af- ter the first and in 4 (3.6%) patients after second interven- tion. Based on Summary score, that change was found in 2 (1.8%) patients after second intervention as compared to baseline (Figure 2). symptoms (Table 1). Also, global health status/QoLs signifi- cantly change only after first intervention (Figure 1). As regards to a change in DLQI score ≥4 and pNRS score ≥4 (thresholds that are widely considered as clinically meaningful changes) 58 (52.7%) and 31 (28.2%) individu- als achieved this level of response in DLQI and pNRS, ac- cordingly after the first intervention, respectively. These rates Figure 1. Boxplots demonstrating QoL scores at baseline and after first and second intervention. Figure 2. Barplots showing significant and non-significant changes in quality of life scores after each intervention. Original Article | Dermatol Pract Concept. 2024;14(3):e2024118 5 QoLs Scales and Baseline Characteristics QoLs scores did not significantly differ in terms of gender, number of doses and personal history of skin disease. The mean (SD) BSA of the patients was 0.41 (0.18) and was not significantly correlated with either QoL scores at baseline. Moreover, individuals experiencing dirAE of higher grades at baseline had more impaired DLQI, pNRS and Summary score as compared to those with lower grades. Analytically, patients with grade 4 toxicities had mean DLQI, pNRS and Summary score 20, 10, 81.2 respectively, while for grade 1 toxicities the corresponding scores were 13, 4.57 and 79.8. There was a significant correlation between age and pNRS Correlation Analysis At baseline, DLQI and pNRS were moderately correlated (rho 0.44, P < 0.001), while DLQI showed weak cor- relation with summary score of EORTC-C30 (rho 0.19, P = 0.04), functional (rho -0.14, P = 0.14) and symptom scores (rho -0.17, P = 0.06), and no correlation with global health status/QoLs (rho 0.01, P = 0.90) (Figure 3). After the first and the second intervention, a weak correlation between DLQI and pNRS remained (rho 0.20, P = 0.02 and rho 0.23, P = 0.01, respectively), whereas summary score, functional or symptoms scores were not correlated with either DLQI or pNRS (Table 2). Figure 3. Scatterplots showing the correlation between Dermatology Life Quality Index and Numerical Rating Scale for pruritus, Global health status and Summary score a) at baseline, b) after 1st intervention and c) after 2nd intervention. Table 2. Correlation analysis between DLQI and other QoL scores. Baseline 1st intervention 2nd intervention Rho P Rho P Rho v DLQI Global Health 0.012 0.90 -0.056 0.56 -0.129 0.17 pNRS 0.441 <0.001 0.227 0.02 0.260 0.01 EORTC-QLQ-C30 Summary score 0.197 0.04 0.064 0.50 0.066 0.49 Functional scale -0.140 0.14 0.056 0.56 -0.061 0.52 Symptom scale -0.177 0.06 -0.047 0.62 -0.074 0.44 DLQI = Dermatology Quality of Life Index; pNRS = numerical rating scale for pruritus; QoL = Quality-of-Life. 6 Original Article | Dermatol Pract Concept. 2024;14(3):e2024118 to individuals managed by non-dermatologists [22]. The aforementioned observations highlight the crucial role of the dermatologist in early diagnosis and successful treatment of dirAEs, towards improvement of patients status and un- impaired oncologic therapy [22]. In addition, the use of the aforementioned scores was useful in detecting clinically sig- nificant changes in QoL after appropriate treatment, in con- trast to the EORTC- C30 and the global health status that appeared insufficient to capture changes related to skin QoL. Data regarding QoL of the oncologic patients treated with ICIs mostly emerge from phase III trials testing effi- cacy and safety of certain immunotherapies [13,18,23-25]. A meta-analysis assessed the difference in QoL between patients under chemotherapy versus ICIs and found that ICIs are as- sociated with a better QoL and a longer time to clinical dete- rioration as compared to chemotherapeutics [25]. QoL in the majority of cancer-drugs trials is assessed by oncology- derived, generic questionnaires, such as the EORTC-QLQ-C30. However, ICIs-derived toxicities differ from those tradition- ally reported with conventional oncologic drugs, rendering the measurement of QoL in the context of ICI treatment par- ticularly challenging. In particular, the impact of cutaneous rash and pruritus that are the most common irAEs, is poorly represented in generic indexes, like SF-36 questionnaire or EORTC-QLQ-C30.Taking into account the aforementioned limitations and considering that real-life data about der- matology QoL of patients experiencing dirAEsare scarce in the literature, we decided to use both, dermatology-derived (DLQI, pNRS) and oncology-derived (EORTC-QLQ-C30) PROs and investigate the correlation between them [13]. Our findings, based on DLQI and pNRS scores, clearly indicate an impairment of patients QoL related to the de- velopment of cutaneous adverse events. However, this ob- servation is not clearly reflected in the EORTC-QLQ-C30. Our findings are in line with the conclusions of a systematic review by Frances et al suggesting that data in existing lit- erature regarding the impact of ICIs on health-related QoL do not adequately capture the impact of cutaneous adverse reactions. The latter indicates that conventional oncologic QoL assessment tools like EORTC-QLQ-30, once devel- oped for capturing the impact mostly of chemotherapy, may be insufficient to capture the impact of newer oncologic treatments. Therefore, dermatology derived questionnaires, like DLQI, pNRS, Skindex7 and ItchyQoL should be inte- grated in clinical practice to better cover this aspect of QoL. Towards overcoming the aforementioned limitations, adapted measurement scales are being developed to improve the assessment of the impact of these life-changing treat- ments on patients QoL [13,23,24,27,28]. A significant observation was that pruritus appears to be a decisive factor in most patients perceived QoL. Mean pNRS in our sample was particularly high at baseline and score at baseline, with an increase of 0.04 in pNRS for every added year of age (b = 0.04, 95% confidence interval [CI] 0.005 – 0.08). Regarding type of primary cancer, there was a statistically significant difference in pNRS and global health QoLs, and from pairwise comparisons, patients with mela- noma had a significantly lower mean pNRS score at baseline, compared to patients with head and neck SCC (mean differ- ence 2.82, P = 0.03) and a higher mean Global health QoLs, respectively. In relation to type of ICI treatment, patients treated with combination therapy had higher DLQI score at base- line (mean DLQI 22.0) compared to patients treated with anti-PD1 (mean 15.1 [5.57], P = 0.001) and patients treated with anti-PDL1 )(mean 15.9 [3.18], P = 0.002). Analysis for Patients with Pruritus Patients with pruritus had a higher mean baseline DLQI (mean 20.27 [3.06]) and pNRS score (mean 8.93 [1.16]) compared to all other individuals (Mann-Whitney t-test, P <0.001 and P < 0.034, respectively). All other scores, in- cluding summary EORTC-C30, functional and symptom scales and global health, did not significantly differ in pa- tients with pruritus, as compared to all other participants. From mixed models, after each intervention, patients with pruritus had higher DLQI score compared to all other patients (4.67, 95%CI 2.07 – 7.28, P < 0.001). DLQI was significantly impaired at baseline, but rapidly improved after adequate therapeutic intervention, as shown in follow-up visits. In a similar manner, pNRS significantly improved from baseline. PNRS moderately correlated with DLQI. Individuals experiencing pruritus reported worse quality of life (higher mean DLQI and mean pNRS com- pared to all other patients at baseline), highlighting that pru- ritus is a key symptom in QoL. Conclusions Skin toxicities occur in up to 50% of patients treated with ICIs. However, publications reporting skin-related QoL in this group are lacking. In this study we evaluatedthe impact of dirAEs on patients QoL, based on DLQI and pNRS in conjunction with EORTC-QLQ-C30, as well as the role of dermatologic intervention towards improvement of QoL. Our main finding was that dirAEs significantly impair pa- tients QoL, with moderate and severe dirAEs resulting in greater impact compared to mild skin toxicities. Furthermore, we showed that adequate dermatologic intervention improved DLQI and pNRS. In a retrospective cohort study, Chen et al pointed out that patients with di- rAEs when managed by dermatologists were less likely to receive systemic immunosuppression and less likely to re- quire ICI discontinuation due to skin toxicity, as compared Original Article | Dermatol Pract Concept. 2024;14(3):e2024118 7 Melanoma: Characteristics of Immune-Related Adverse Events and Association with Outcomes Nivolumab in Metastatic Melanoma: irAE Relation to Survival. Clin Cancer Res 2016; 22: 886–94. 11. Nagao A, Takei Y, Ogawa Y, Shimada M, Tanigawa K, Suzuki S. Examination of the quality of life in the cancer patients under immunotherapy. Gan To Kagaku Ryoho 2012; 39: 1785–7. 12. Lins L, Carvalho FM. SF-36 total score as a single measure of health-related quality of life: Scoping review. SAGE Open Med [Internet]. 2016 Oct 4 [cited 2020 Oct 15];4. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5052926/ 13. 13 O’Reilly A, Hughes P, Mann J et al. An immunotherapy sur- vivor population: health-related quality of life and toxicity in patients with metastatic melanoma treated with immune check- point inhibitors. Support Care Cancer 2020; 28: 561–70. 14. Finlay AY, Khan G. Dermatology Life Quality Index (DLQI)—a simple practical measure for routine clinical use. Clin Exp Der- matol 1994; 19: 210–6. 15. Cella D, Grünwald V, Nathan P et al. Quality of life in patients with advanced renal cell carcinoma given nivolumab versus everolimus in CheckMate 025: a randomised, open-label, phase 3 trial. Lancet Onco. 2016; 17: 994–1003. 16. Aaronson NK, Ahmedzai S, Bergman B et al. The European Or- ganization for Research and Treatment of Cancer QLQ-C30: a quality-of-life instrument for use in international clinical trials in oncology. J Natl Cancer Inst. 1993; 85: 365–76. 17. De Luca R, Coco GL, Addeo R et al. Quality of Life in Patients With Severe Skin Reactions in Course of First-Generation Epi- dermal Growth Factor Receptor Inhibitors Monoclonal Anti- bodies (Our Experience With Cetuximab). World J Oncol 2021; 12: 104. 18. Barbu MA, Niţipir C, Voiosu T, Giurcăneanu C. Impact of der- matologic adverse reactions on QOL in oncologic patients: re- sults from a single-center prospective study. Rom J Intern Med 2018; 56: 96–101. 19. Mazieres J, Kowalski D, Luft A et al. Health-related quality of life with carboplatin-paclitaxel or nab-paclitaxel with or without pembrolizumab in patients with metastatic squamous non-small- cell lung cancer. J Clin Oncol 2020; 38: 271–280. Ooki, A, Morita S, Tsuji A, et al. Disagreement between patient- and physician-reported outcomes on symptomatic ad- verse events as poor prognosis in patients treated with first-line cetuximab plus chemotherapy for unresectable metastatic col- orectal cancer: Results of Phase II QUACK trial. Cancer Med 2000; 9: 9419–9430. 20. Basra MK, Salek MS, Camilleri L, Sturkey R, Finlay AY. Deter- mining the minimal clinically important difference and respon- siveness of the Dermatology Life Quality Index (DLQI): further data. Dermatology 2015; 230: 27–33. 21. Chen ST, Molina GE, Lo JA et al. Dermatology consultation re- duces interruption of oncologic management among hospitalized patients with immune-related adverse events: a retrospective co- hort study. J Am Acad Dermatol 2020; 82: 994–6. 22. Walocko FM, Ly BC, White MS, Chen SC, Yeung H. Health- related quality of life measures and immune checkpoint inhibitors: a systematic review. J Am Acad Dermatol 2020; 82: 1004–6. 23. Barrios DM, Phillips GS, Freites-Martinez A et al. Outpatient derma- tology consultations for oncology patients with acute dermatologic adverse events impact anticancer therapy interruption: a retrospec- tive study. J EurAcad Dermatol Venereol 2020; 34: 1340–1347. correlated with DLQI, indicating that pruritus plays a key role in QoL. Given that currently available treatments can only moderately control severe ICI-derived pruritus, the de- velopment of new therapeutic interventions, or combined treatment strategies for pruritus,are highly needed. Interestingly, a recent study showed that regular record- ing of PROs demonstrated a 5-month overall survival bene- fit for patients with metastatic solid tumors,as compared to patients receiving standard care [29,20]. The latter highlights the benefits of incorporating tools that adequately capture patients health status in our daily practice and the need of a more patient-centric medicine. Although correlating overall survival with QoL monitoring was not in the aims of the current study, we strongly believe that outlining the patients profile with the use of PROs improves treatment- decision making. In conclusion, our study confirmed the significant impact of dirAEs on patients QoL and the important role of the dermatologist in managing ICI-derived skin toxicities. 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