Prevalence of dermatological toxicities in patients with melanoma undergoing immunotherapy: Systematic review and meta-analysis

Náthali Felícia Mineiro dos Santos Garrett; Ana Cristina Carvalho da Costa; Elaine Barros Ferreira; Giovanni Damiani; Paula Elaine Diniz dos Reis; Christiane Inocêncio Vasques

doi:10.1371/journal.pone.0255716

. 2021 Aug 6;16(8):e0255716. doi: 10.1371/journal.pone.0255716

Prevalence of dermatological toxicities in patients with melanoma undergoing immunotherapy: Systematic review and meta-analysis

Náthali Felícia Mineiro dos Santos Garrett ^1,^#, Ana Cristina Carvalho da Costa ^2,^#, Elaine Barros Ferreira ^1,^‡, Giovanni Damiani ^3,^4,^5,^6,^‡, Paula Elaine Diniz dos Reis ^1,^‡, Christiane Inocêncio Vasques ^1,^*,^#

Editor: Gayle E Woloschak⁷

PMCID: PMC8345892 PMID: 34358260

Abstract

Background

Checkpoint inhibitors have revolutionized advanced melanoma care; however, their cutaneous side effects have not been definitively elucidated.

Objective

To identify the prevalence of cutaneous toxicity in patients with melanoma treated with immune checkpoint inhibitors as monotherapy and/or in combination with chemotherapy and/or radiotherapy.

Materials and methods

We performed a systematic review and meta-analysis, which encompassed both clinical trials and observational studies describing the dermatological toxicities in patients treated with immune checkpoint inhibitors. The protocol was registered in the International Prospective Register of Systematic Review under the number CRD42018091915. The searches were performed using the CINAHL, Cochrane CENTRAL, LILACS, LIVIVO, PubMed, Scopus, and Web of Science databases. The methodological quality of the studies was evaluated with the JBI Critical Appraisal Checklist for Studies Reporting Prevalence Data

Results

A total of 9,802 articles were identified in the databases. The final sample comprised 39 studies. The evaluated drugs were ipilimumab, tremelimumab, pembrolizumab, and nivolumab. The results suggest that the most prevalent side effect was grade 1 and 2 pruritus (24%), followed by grade 1 and 2 rash (21%) and grade 1 and 2 vitiligo (10%).

Conclusion

The most prevalent side effects in patients treated with checkpoint inhibitors are pruritus, rash, and vitiligo, and they are rated mostly as grades 1 and 2 adverse events. Remarkably, vitiligo is most commonly found in patients treated with PD-1 inhibitors.

Introduction

Immune checkpoint inhibitors (ICIs), which were originally introduced for the treatment of melanoma during the last decade, have revolutionized cancer therapy [1,2]. Many patients have been living longer due to remarkable responses and delay of disease progression during ICI treatment [3].

Unlike monoclonal antibodies, ICIs act as co-stimulatory inhibitory receptor antagonists to counteract the deactivation of the immune system caused by the tumor and to promote immune activation [4,5]. The majority of ICIs act on the inhibition of cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4), programmed cell death protein 1 (PD-1), and programmed death-ligand 1 (PD-L1) [6].

Although in many cancers one can see anti-tumor activity with ICIs and traditional chemotherapy, the types, mechanisms, and rates of side effects differ [7,8]. The side effects related to ICIs are labeled as immune-related adverse events (irAEs) and are thought to be related to the inflammatory response caused in several organs due to the stimulation of the immune system, especially of T cells [9–11]. Though one can see irAEs involving all body systems, cutaneous toxicity is of particular interest.

The dermatological toxicity of ICIs is similar, although its incidence is higher with ipilimumab than with anti-PD-1 or anti-PD-L1 agents [12,13]. Cutaneous adverse events (AEs) attributed to CTLA-4 inhibitors usually occur within 3–6 weeks after the initiation of therapy. However, these AEs occur within 2–10 months with PD-1 and PD-L1 inhibitor therapy [14].

The cost associated with the management of dermatological toxicity in patients with metastatic melanoma reaches US $ 21,726.00 per month, which represent the total adjudicated amount paid to all providers for inpatient and outpatient services and drugs [15]. Therefore, understanding the risks for dermatological toxicity can help to identify cutaneous AEs early on and thus to enable a more assertive clinical management, in addition to reducing costs.

Previous systematic reviews have assessed the patterns of irAEs and the safety of one or more ICIs [1,16–19]. However, several previous studies limited the search of references in the databases to a specific period [1,16,17,19], whereas another study restricted the review to only a few ICIs [18].

This review is a comprehensive report on the prevalence of dermatological toxicity in patients with melanoma using ICIs as monotherapy and/or in combination with chemotherapy and/or radiotherapy.

Materials and methods

Protocol and registration

This systematic review was elaborated according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses Checklist (PRISMA) [20]. The protocol was registered in the International Prospective Register of Systematic Review (PROSPERO) [21] under the number CRD42018091915.

Eligibility criteria

This review aimed to answer the following guiding question, based on the PECO strategy—Population, Exposure, Control and Outcomes: “What is the prevalence of dermatological toxicity (O) in patients with melanoma (P) undergoing treatment with ICIs (E)?”

We included clinical trials (randomized and non-randomized) and observational studies that evaluated melanoma cancer patients undergoing treatment with a single ICI, a combination of ICIs, or a combination of an ICI with chemotherapy and/or radiotherapy and that described the prevalence of dermatological toxicity. There were no restrictions regarding the language or publication period.

The studies were analyzed for inclusion and exclusion criteria in two phases. In phase 1 (screening of the titles and abstracts), we excluded studies that evaluated children and adolescents with cancer; adult oncology patients treated with ICIs with an associated autoimmune disease; and adult oncology patients treated with ICIs who also received vaccines, target therapy, or other therapies. Further, we excluded studies with cutaneous toxicity not associated with the use of ICIs, studies showing other (non-dermatological) toxicities associated with the use of ICIs, literature reviews, letters, case reports, personal opinions, conferences, abstracts, and book chapters.

In phase 2 (full text reading), we excluded studies that presented complementary data from previously published investigations, qualitative studies, studies that did not present complete data and/or did not allow the extraction of the data of interest, and studies that evaluated other types of cancer (not melanoma).

Information sources

The searches were carried out in the following electronic databases: CINAHL, Cochrane CENTRAL, LILACS, LIVIVO, PubMed, Scopus, and Web of Science. A search strategy was developed for each of the databases (S1 File). The gray literature was also checked using Google Scholar and Open Gray. Further, a manual search was performed on the list of references of the included studies. All searches were performed on January 23, 2019.

Study selection

The study selection was carried out in two phases. In phase 1, two reviewers (N.F.M.S.G. and A.C.C.C.) independently assessed the titles and abstracts of all citations identified in the electronic databases. Articles that did not meet the inclusion criteria were excluded. This step was performed on a Rayyan web application [22]. In phase 2, the same reviewers applied the inclusion criteria to the full text of the articles. Any disagreements in the first or second phase were resolved by discussion until an agreement was reached between the two authors. When consensus could not be reached, the third reviewer (C.I.V.) was asked to evaluate the article and make the final decision.

References, including the removal of duplicates, were managed in EndNoteBasic [23].

Data collection process

Two reviewers (N.F.M.S.G. and A.C.C.C.) independently collected data from the selected studies. A third reviewer (C.I.V.) evaluated the accuracy of the collected information. For all included studies, the following information was recorded: study characteristics (author, year, country of publication, study design, and purpose); sample characteristics (sample size and mean age of the participants); duration of the drug treatment and follow-up; and characteristics of the results (type of dermatological toxicity and main conclusions).

Risk of bias in individual studies

To evaluate the risk of bias, the JBI Critical Appraisal Checklist for Studies Reporting Prevalence Data [24], composed of nine items, was used. For each of the items, it was possible to check “yes”, “no”, “unclear”, or “not/applicable”.

The methodological quality of the studies was categorized as low risk of bias (70% or more “yes” responses), moderate risk of bias (50%–69% “yes” responses), and high risk of bias (up to 49% “yes” responses).

Summary measures

The frequency of dermatological toxicity described by the studies was considered the primary outcome. The frequency was expressed as a percentage, which corresponds to the number of cases present among all patients treated with ICIs. We analyzed the toxicities with highest prevalence in the studies, allowing associative measures such as rash, pruritus, and vitiligo.

Synthesis of the results

The meta-analysis was performed using the Jamovi software, version 1.6, which offers a variety of statistical techniques [25]. The prevalence was estimated by the number of events out of the total sample. We considered the homogeneity of the studies in relation to the type of exposure and outcome. Heterogeneity was calculated using I². An I² value greater than 50% was considered a substantial indicator of heterogeneity among the studies, and a random effect model could be used. When I² is less than 50%, a fixed effect model is recommended. Jamovi provides fixed and random effect models for each analysis, and we therefore chose between the two based on the I² values. Beside the I² values, we also considered the Confidence Interval and the p value. The level of significance was set at 0.05. Funnel plot was not considered, since it is a prevalence systematic review, and the graphic results could be non interpretability [26].

Results

Study selection

In phase 1, 9,802 studies were identified in the seven electronic databases. Among the 7,484 articles that remained after the removal of duplicates, 218 were selected. Another five studies that were identified in the gray literature were added and continued to phase 2. No additional study was identified in the list of references of the included articles.

Among the 223 studies that followed into Phase 2, 184 articles were excluded (S2 File). Thus, 39 studies [27–65] that met the eligibility criteria were included in the qualitative synthesis. Among these, 35 studies were considered adequate for the meta-analysis. The process of identification, inclusion, and exclusion of studies is described in Fig 1.

Characteristics of the studies

The articles were published in English, except for one study, which was published in Spanish [39]. The publications occurred between 2008 and 2018, with the highest number of publications in 2017. There were predominantly multicenter studies (n = 13) [28,30,32,36,41,45–48,51,55,60,61] and studies conducted in the United States (n = 11) [27,29,31,33,35,37,38,41,42,56,64]. With respect to the study design, there were 28 clinical trials (randomized or non-randomized) [27–31,33,35,37,38,40–48,51,55,56,58–64] and 11 observational studies [32,34,36,39,49,50,52–54,57,65].

Regarding the treatment with ICIs, 23 studies evaluated the use of ICIs alone, including the use of tremelimumab (n = 1) [28], ipilimumab (n = 14) [27,29,31,32,34,36,39,44,45–47,51–53], nivolumab (n = 4) [50,54,59,60], and pembrolizumab (n = 4) [33,49,58,61]. Combinations of two ICIs were evaluated in eight studies, including the combinations ipilimumab + nivolumab (n = 6) [38,41,48,63–65] and ipilimumab + pembrolizumab (n = 1) [57]. Finally, the combination or comparison of ICIs with chemotherapy was assessed by six studies (n = 6) [30,35,37,40,42,62]. The characteristics of the studies included in the review are described in Table 1.

Table 1. Studies included in the review according to methodological characteristics (n = 39).

Author, Year Country	Study design	Sample size (n)	Age in years (mean and range)	Drug (dose and schedule)	Dermatological toxicities (n) %
ALTOMONTE et al, 2013 [32] Multicentric	Retrospective OS	74	56 (23–79)	IPI 10 mg/kg administered intravenously over 90 min, every 3 weeks, for a total of four doses Maintenance therapy: IPI 10 mg/kg every 12 weeks	Grade 1 or 2 Pruritus: (13) 17.6% Rash: (7) 9.4% Dermatitis: (1) 1.3%
ASCIERTO et al, 2017 [51] Multicentric	RCT, phase 3	727 10 mg/kg group (365) 3 mg/kg group (362)	IPI (10 mg/kg): 62 (49–70) IPI (3 mg/kg): 62 (51–71)	IPI: 3 mg/kg IPI: 10 mg/kg Drug was administered by intravenous infusion for 90 min every 3 weeks for four doses	IPI (3 mg/kg) Grade 1or 2 Rash: (48) 13% Pruritic rash: (3) 1% Maculopapular rash: (4) 1% Pruritus: (79) 22% Grade 3 or 4 Rash: (2) 1% Pruritic rash: (1) <1% Pruritus: (2) 1% Erythema nodosum: (1) <1% Toxic skin eruption: (1) <1%	IPI (10mg/kg) Grade 1 or 2 Rash: (90) 25% Pruritic rash: (5) 1% Maculopapular rash: (3) 1% Pruritus: (80) 22% Toxic skin eruption: (1) <1% Grade 3 or 4 Rash: (5) 1% Maculopapular rash: (1) <1% Pruritus: (2) 1%
CAMACHO et al, 2009 [28] Multicentric	NRCT, phase 1 RCT, phase 2	117 28 (Phase 1) 89 (Phase 2)	Phase 1: not described Phase 2: 57.5 (20–83	Tremelimumab Phase 1: at a dose of 3, 6 or 10 mg/kg (intravenous infusion once every 28 days) Phase 2: at a dose of 10 mg/kg (intravenous infusion monthly) or 15 mg/kg (intravenous infusion every 3 months)	Phase 1–3 mg/kg: Grade 1 or 2 Rash: (1) 33% Pruritus: (1) 33% Phase 1–6 mg/kg: Grade 1 or 2 Rash: (1) 33% Pruritus: (1) 33% Phase 1–10 mg/kg: Grade 1 or 2	Rash: (10) 46% Pruritus: (10) 46% Phase 2–10 mg/kg: Grade 1 or 2 Rash: (15) 34% Pruritus: (13) 30% Phase 2–15 mg/kg: Grade 1 or 2 Rash: (16) 36% Pruritus: (15) 33%
DIKA et al, 2017 [52] Italy	Prospective OS	41	Not described	IPI at a dose of 3 mg/kg with 3 weeks interval.	Grade 1 or 2 Rash: (3) 7.2% Folliculitis: (3) 7.2% Folliculitis: (2) 4.8% Vitiligo: (2) 4.9% Mucositis: (1) 2.4% Rosacea: (1) 2.4% Eczema: (1) 2.4% Acneiform eruption: (1) 2.4%	Syringometaplasia mucinosa (1) 2.4% Grade 4 Stevens-Johnson syndrome: (1) 2.4% Not classification Pruritus: (4) 9.8% Xerosis: (2) 4.9%
EGGERMONT et al, 2016 [47] Multicentric	RCT, phase 3	951 IPI (475) Placebo (476)	51.5 (18–84)	IPI (intravenously at a dose of 10 mg/kg every 3 weeks, for 4 doses) Placebo (every 3 weeks, for 4 doses)	IPI (n = 471) Grade 1 or 2 Rash: (156) 33.1% Any dermatologic event: (278) 59.02% Grade 3 Rash: (5) 1.1% Any dermatologic event: (20) 3.2%	Placebo (474) Grade 1 or 2 Rash: (52) 11,6% Any dermatologic event: (99) 20.8% Grade 3 Rash: 0 Any dermatologic event:0
EGGERMONT et al, 2018 [61] France	RCT	1.019 Pembrolizumab (514) Placebo (505)	Pembrolizumab 54 (19–88) Placebo 54 (19–83)	Pembrolizumab (200mg) or Placebo intravenously every 3 weeks for a total of 18 doses (approximately 1 year)	Pembrolizumab Any Grade Rash: (82) 16.1% Pruritus: (90) 17.7% Severe skin reactions: (3) 0.6% Vitiligo: (24) 4.7% Grade >3 Rash: 1 (0.2) Severe skin reactions: (3) 0.6%	Placebo Any Grade Rash: 54 (10.8) Pruritus: 51 (10.2) Vitiligo: (8) 1.6% Grade <3 Rash (156) 33.1%
HAMID et al, 2013 [33] USA	NRCT	135	60,4 (25–94)	Lambrolizumab (10 mg/kg) 30 min intravenous infusion, every 2 weeks, 2 mg/kg, 30 min intravenous infusion, every 3 weeks or 10 mg/kg, 30 min intravenous infusion, every 3 weeks.	Grade 1 or 2 Rash: (25) 18.5% Pruritus (27) 20% Vitiligo (12) 9%	Grade 3 or 4 Rash: (3) 2% Pruritus: (1) 1%
HODI et al, 2016 [48] Multicentric	RCT, phase 2	142 Nivolumab + IPI (95) IPI (47)	Not described	Nivolumab 1 mg/kg plus IPI 3 mg/kg or IPI 3 mg/kg plus placebo, every 3 weeks for four doses. Subsequently, patients assigned to nivolumab plus IPI received nivolumab 3 mg/kg every 2 weeks	Nivolumab + IPI Grade 1 or 2 Rash: (36) 38% Maculopapular rash: (12) 13% Pruritus: (37) 39% Grade 3 or 4 Rash: (4) 4% Maculopapular rash: (3) 3% Pruritus: (1) 1%	IPI Grade 1or 2 Rash: (14) 30% Maculopapular rash: (6) 13% Pruritus: (15) 33%
HUA et al, 2016 [49] France	Prospective OS	67	54 (20–74)	Pembrolizumab (administered intravenously every 2 or 3 weeks at a dose ranging from 2 to 10 mg/kg).	Grade 1 or 2 Vitiligo: (17) 25% Pruritus: (16) 24% Eczematiform, lichenoid, or psoriasiform skin irritation: (18) 27%
JUNG et al, 2017 [53] Korea	Retrospective OS	104	58 (50–66)	IPI (intravenously at a dose of 3 mg/kg, every 3 weeks) 4 cycles.	Grade 1 or 2 Rash: (22) 21.1% Pruritus (32) 30.8%	Grade 3 Rash: (1) 1% Pruritus: (1) 1%
KU et al, 2010 [29] USA	NRCT	51	62 (38–86)	IPI (intravenously at a dose of 10 mg/kg every 3 weeks, over 90 min, for 4 doses) maintenance ipilimumab 10 mg/kg every 12 weeks.	Grade 1 or 2 Pruritus: (22) 43% Rash: (18) 35%	Grade 3 Rash: (1) 2%
LARKIN et al, 2018 [62] England	RCT, phase 3	405 Nivolumab (272) ICC (133)	Nivolumab: 59 (23–88) ICC: 62 (29–85)	Nivolumab 3mg/kg intravenously every 2 weeks or ICC (DTIC 1,000 mg/m2 every 3 weeks or carboplatin area under the curve 6 plus paclitaxel 175 mg/m2 every 3 weeks)	Nivolumab Any grade Pruritus: (59) 22% Rash: (36) 13% Vitiligo: (29) 11% Maculopapular rash: (19) 7% Dry skin: (15) 6% Grade 3 or 4 Rash: (1) <1% Maculopapular rash: (1) <1%	ICC Any grade Pruritus: (1) 1% Rash: (5) 5% Maculopapular rash: (2) 2%
LONG^a et al, 2017 [54] Australia	Retrospective OS	306 Non-beyond Progression (221) Beyond progression (85)	62 (18–90)	Nivolumab (3mg/kg every 2 weeks)	Non-treatment beyond Progression (Non-TBP) Any Grade Pruritus: (25) 11% Rash: (23) 10% Grade 3 or 4 Pruritus: (1) <1% Rash: 0	Treatment Beyond Progression (TBP) Any Grade Pruritus: (23) 27% Rash: (23) 27% Grade 3 or 4 Pruritus: 0 Rash: 0
LONG^b et al, 2017 [55] Multicentric	NRCT, phase 1b	153	60 (53–70)	Pembrolizumab (2 mg/kg) intravenously for 30 min once every 3 weeks followed by IPI (1 mg/kg) intravenously for 90 min once every 3 weeks for four doses, followed by pembrolizumab 2 mg/kg intravenously for 30 min every 3 weeks for up to 2 years.	Treatment-related AEs Grade 1 or 2 Rash: (60) 39% Pruritus: (63) 41% Vitiligo: (30) 20% Rash Maculopapular: (18) 12% Pruritic rash: (7) 5% Macular rash: (6) 4% Drug eruption: (4) 3% Grade 3 or 4 Rash: (4) 3% Pruritus: 0 Rash Maculopapular: (1) 1% Pruritic rash: (2) 1% Macular rash: (1) 1% Drug eruption: (2) 1% DRESS syndrome: (1) 1% Pemphigoid: (1) 1%	irAEs Grade 1 or 2 Skin reactions: (1) 1% Grade 3 or 4 Skin reactions: (12) 8%
MARGOLIN et al, 2012 [31] USA	NRCT, phase 2	72 Cohort A (n = 51) Cohort B (n = 21)	Cohort A: 59 (33–79) Cohort B: 57 (30–74)	IPI (10 mg/kg) four doses, intravenous, one every 3 weeks. (designated weeks 1, 4, 7, and 10; induction). Patients who were clinically stable at 24 weeks were eligible to continue with treatment with IPI 10 g/kg every 12 weeks (maintenance).	Cohort A Grade 1 and 2 Rash: (17) 33% Pruritus: (16) 31% Grade 3 or 4 Rash: (1) 2% Pruritus: 0	Cohort B Grade 1 and 2 Rash: (6) 29% Pruritus: (5) 24% Grade 3 or 4 Rash: (1) 5% Pruritus: 0
RUIZ-MORALES et al, 2014 [39] Mexico	Retrospective OS	10	49 (± 25)	IPI (3mg/kg) intravenous, during 90 min infusion every 3 weeks, with a total of 4 scheduled doses.	Grade 1 and 2 Pruritus: (3) 30% Rash: (2) 20%	Grade 3 and 4 Pruritus: 0 Rash: 0
NAKAMURA et al, 2016 [50] Japan	Retrospective OS	35	67 (40–85)	Nivolumab (intravenously at a dose of 2 mg/kg, every 3 weeks)	Grade 1 or 2 Vitiligo: (9) 25.7%
NAMIKAWA et al, 2018 [63] Multicentric	NRCT	30	58.5 (31–81)	Nivolumab (1 mg/kg) plus IPI (3 mg/kg) every 3 weeks for four doses, followed by biweekly doses of nivolumab (3 mg/kg)	Grade 1 and 2 Rash: (18) 60% Pruritus: (10) 33% Rash maculopapular: (4) 13%	Grade 3 or 4: Rash: (2) 7% Pruritus: 0 Rash maculopapular: (1) 3%
POSTOW et al, 2013 [34] Multicentric	Retrospective OS	33 25 (3 mg/kg) 8 patients (10 mg/kg)	65 (35–90)	IPI (intravenously at a dose of 3 mg/kg, every 3 weeks or at a dose of 10 mg/kg).	IPI 3 mg/kg: Grade 1 and 2 Rash: (4) 15%	IPI 10 mg/kg: Grade 1 and 2 Rash: (2) 25%
POSTOW et al, 2015 [41] USA	RCT	142 Nivolumab + IPI (95) IPI (47)	65 (27–87)	IPI 3 mg/kg combined with either nivolumab 1 mg/kg or placebo every 3 weeks for 4 doses, followed by nivolumab 3 mg/kg or placebo every 2 weeks	Nivolumab + IPI Grade 1–2 Rash: (39) 41.5% Maculopapular rash (15) 16% Pruritic rash (3) 3.2% Pruritus: (33) 35.1% Vitiligo: (10) 10.6% Grade 3 or 4 Rash: (5) 5% Maculopapular rash (3) 3% Pruritus: (1) 1.1%	IPI Grade 1–2 Rash: (12) 26.1% Maculopapular rash (8) 17.4% Pruritic rash (5) 10.9% Pruritus: (13) 28.3% Vitiligo: (4) 8.7%
RIBAS et al, 2013 [35] USA	RCT, phase 3	655 Tremelimumab (328) Chemotherapy (327)	Tremelimumab: 57 (22–90) Chemotherapy: 56 (22–90)	Tremelimumab (15 mg/kg once every 90 days to four cycles) or DTIC (1,000 mg/m2) IV on day 1 of a 21-day cycle or single-agent Temozolomide (200 mg/m2) orally on days 1 to 5 of a 28-day cycle	Tremelimumab Any Grade Rash: (106) 33% Pruritus: (100) 31% Grade >3 Rash: (7) 2% Pruritus: (3) 1%	Chemotherapy Any Grade Rash: (17) 5% Pruritus: (16) 5% Grade >3 Rash: (1) <1% Pruritus: 0
RIBAS et al, 2015 [42] USA	RCT, phase 2	540 Pembrolizumab 2 mg/kg (180) Pembrolizumab 10 mg/kg (181) Chemotherapy control (179)	Pembrolizumab 2 mg/kg: 62 (15–87) Pembrolizumab 10 mg/kg: 60 (27–89) Chemotherapy: 63 (27–87)	Pembrolizumab 2 mg/kg or 10 mg/kg every 3 weeks or investigator-choice chemotherapy (paclitaxel plus carboplatin, paclitaxel, carboplatin, DTIC, or oral temozolomide).	Pembrolizumab 2 mg/kg Grade 1 or 2 Pruritus: (37) 21% Rash: (21) 12% Vitiligo: (10) 6% Dry skin: (9) 5% Grade 3 or 4 Pruritus: 0 Rash: 0 Vitiligo: 0 Dry skin: 0 Pembrolizumab 10 mg/kg Grade 1 or 2 Pruritus: (42) 23% Rash: (18) 10% Vitiligo: (9) 5%	Dry skin: (9) 5% Grade 3 or 4 Pruritus: 0 Rash: 0 Vitiligo: 0 Dry skin: 0 Chemotherapy Grade 1or 2 Pruritus: (6) 4% Rash: (8) 5% Vitiligo: (2) 1% Dry skin: (2) 1% Grade 3 or 4 Pruritus: 0 Rash: 0 Vitiligo: 0 Dry skin: 0
ROBERT et al, 2011 [30] Multicentric	RCT, phase 3	502 IPI plus DTIC (250) Placebo plus DTIC (252)	IPI plus DT: 57.5 Placebo plus DTIC: 56.4	IPI (10 mg/Kg) + DTIC (850 mg per square meter) or Placebo (given at weeks 1, 4, 7, and 10) + DTIC (850 mg per square meter)		irAEs: IPI plus DTIC Total Pruritus: (66) 26.7% Rash: (55) 22.3% Grade 3 or 4 Pruritus: (5) 2% Rash: (3) 1.2% Placebo plus DTIC Total Pruritus: (15) 6% Rash: (12) 4.8% Grade 3 or 4 Pruritus: 0 Rash: 0
ROBERT et al, 2014 [40] France	RCT	418 Nivolumab (210) DTIC (208)	Nivolumab: 64 (18–86) DTIC: 66 (26–87)	Nivolumab (3 mg/kg of body weight every 2 weeks and DTIC-matched placebo every 3 weeks) or DTIC (1,000 mg per square meter of body-surface area every 3 weeks and nivolumab-matched placebo every 2 weeks)	Nivolumab Any grade Pruritus: (35) 17% Rash: (31) 15% Vitiligo: (22) 10.7% Grade 3 or 4 Pruritus: (1) 0.5% Rash: (1) 0.5% Vitiligo: 0	DTIC Any grade Pruritus: (11) 5.4% Rash: (6) 2.9% Vitiligo: (1) 0.5% Grade 3 or 4 Pruritus: 0 Rash: 0 Vitiligo: 0
ROBERT et al, 2015 [43] France	RCT	834 Pembrolizumab every 2 Weeks (279) Pembrolizumab every 3 Weeks (277) IPI (278)	Pembrolizumab every 2 Weeks: 61 (18–89)	Pembrolizumab (at a dose of 10 mg/kg of body weight) every 2 weeks or every 3 weeks or four doses of IPI (at 3 mg/kg) every 3 weeks.	Pembrolizumab every 2 Weeks Any grade Rash: (41) 14.7% Pruritus: (40) 14.4% Vitiligo: (25) 9.0% Grade 3–5 Rash: 0 Pruritus: 0 Vitiligo: 0 Pembrolizumab every 3 Weeks Any grade Rash: (37) 13.4% Pruritus: (39) 14.1% Vitiligo: (31) 11.2%	Grade 3–5 Rash: 0 Pruritus: 0 Vitiligo: 0 IPI Any grade Rash: (37) 14.5% Pruritus: (65) 25.4% Vitiligo: (4) 1.6% Grade 3–5 Rash: (2) 0.8% Pruritus: (1) 0.4% Vitiligo: 0
SHOUSHTARI et al, 2018 [64] USA	NRCT	64	56 (22–82)	Intravenous nivolumab (1mg/kg) and IPI (3mg/kg) administered every 3 weeks for up to 4 doses, followed by nivolumab (3mg/kg) every 2 weeks or pembrolizumab (2mg/kg) every 3 weeks	Nivolumab + IPI Grade 1 or 2 Rash/pruritus: (13) 21% Grade 3 or 4 Rash/pruritus: (5) 8% Immune Related- AEs Rash/pruritus: (11 of 18) 61%	Anti- PD-1 Monotherapy Grade 2 Rash/pruritus: (2) 3% Grade 3 or 4 Rash/pruritus: 0 Immune Related- AEs Rash/pruritus: (10) 16%
SOLDATOS et al, 2018 [65] Germany	Retrospective OS	7,770 (number of AEs a certain occurrence was observed)	Not described	IPI only, Nivolumab only, IPI and nivolumab (dose and schedule, not described)	Nivolumab (n = 890 AEs) Rash: (38) 5.6% IPI (n = 2,704 EAs) Rash: (176) 6.5% Pruritus: (79) 2.9%	IPI and nivolumab (n = 682 AEs) Rash: (38) 5.6% Pruritus: (19) 2.8%
VOSKENS et al, 2013 [36] Multicentric	Retrospective OS	752	60.1 (38–81)	IPI (not described)	DRESS syndrome: (1) 4.3%) Photosensitivity reaction: (1) 4.3% Skin toxicity: (1) 4.3% Pyoderma gangraenosum-like ulceration: (1) 4.3% Acneiform rash: (3) 13% Lichenoid exanthema: (1) 4.3% Pruritus: (8) 34.8%	Hypopigmentation: (8) 34.8% Maculopapular exanthema: (3) 13% Pruritic eczema: (1) 4.3%
WEBER et al, 2008 [27] USA	NRCT, Phase 1/2	88 Group A-MD (34) Group A-SD (30) Group B (24)	Group A-MD: 59(34–79) Group A-SD: 57(29–87) Group B: 59.5(33–80)	IPI was administered intravenously over 90 min. IPI up to 20 mg/kg (group A, SD), multiple doses up to 5 mg/kg (group A, MD), and multiple doses up to 10 mg/kg (group B)	All patients Any grade 3 or 4 Rash: (2) 2.3% Vitiligo: (1) 1.1% Group A-MD Any grade 3 or 4 Rash: 0 Vitiligo: (1) 2.9%	Group A-SD Any grade 3 or 4 Rash: 0 Vitiligo: 0 Group B Any grade 3 or 4 Rash: (2) 8.3% Vitiligo: 0
WEBER et al, 2013 [37] USA	RCT, phase 1	59 IPI group (20) IPI-DTIC group (19) IPI–carboplatin- paclitaxel group (20)	56 (64–36)	IPI (10mg/kg) every 3 weeks for up to 4 doses. D group DTIC (850 mg/m2) every 3 weeks. CP group Paclitaxel (175 mg/m2) and carboplatin, every 3 weeks	IPI group Any grades Rash: (16) 80% Pruritus: (11) 55% IPI- DTIC group Any grades Rash: (9) 47.4% Pruritus: (13) 68.4%	IPI–carboplatin- paclitaxel group Any grades Rash: (15) 75% Pruritus: (13) 65% Overall Any grades Rash: (43) 72.9% Pruritus: (39) 66.1%
WEBER et al, 2017 [56] USA	RCT, phase 3	906 3 mg/kg (453) 10 mg/kg (453)	Nivolumab 56 (19–83) IPI 54 (18–86)	Nivolumab at a dose of 3 mg/kg of body weight every 2 weeks or IPI at a dose of 10 mg/kg every 3 weeks for four doses and then every 12 weeks.	Nivolumab N = 453 Any grade Pruritus: (105) 23.2% Rash: (90) 19.9% Maculopapular rash (24) 5.3% Grade 3 or 4 Rash: (5) 1.1%	IPI N = 453 Any grade Pruritus: (152) 33.6% Rash: (133) 29.4% Maculopapular rash (50) 11% Grade 3 or 4 Pruritus: (5) 1.1% Rash: (14) 3.1% Maculopapular rash (9) 2%
WEN et al, 2017 [57] China	Retrospective OS	52	53 (20–78)	IPI (n = 14) (intravenously at a dose of 3 mg/kg every 3 weeks, for 4 cycles) Pembrolizumab (n = 28) (intravenously at a dose of 2 mg/kg every 3 weeks, for 4 cycles) Pembrolizumab plus IPI (n = 10) (IPI intravenously at a dose of 3 mg/kg + Pembrolizumab 1 mg/kg, every 3 weeks, for 4 cycles)	IPI (n = 14) Grade 1 or 2 Pruritus: (4) 29% Rash: (3) 21% Pembrolizumab (n = 28) Grade 1 or 2 Pruritus: (3) 11% Rash: (3) 11% Vitiligo: (5) 18%	Grade 3 or 4 Rash (1) 4% Pembrolizumab + IPI (n = 10): Grade 1 or 2 Pruritus: (5) 50% Rash: (4) 40% Vitiligo: (2) 20%
WOLCHOCK et al, 2013 [38] USA	NRCT	86 Concurrent Treatment (53) Sequenced treatment (33)	Concurrent Treatment 58 (22–79) Sequenced Treatment 64 (23–89)	Concurrent Treatment Cohort 1 (0.3 mg of nivolumab and 3 mg of IPI) Cohort 2 (1 mg of nivolumab and 3 mg of IPI) Cohort 2ª (3 mg of nivolumab and 1 mg of IPI) Cohort 3 (3 mg of nivolumab and 3 mg of IPI) Cohort 4 (10 mg of nivolumab and 3 mg of IPI) Cohort 5 (10 mg of nivolumab and 10 mg of IPI) Sequenced-regimen: Cohorts 6 and 7 (1 mg and 3 mg of nivolumab), every 2 weeks for up to 48 doses.	All patients in concurrent-Regimen All grades: Rash: (29) 55% Pruritus: (25) 47% Urticaria: (1) 2% Blister: (1) 2% Grade 3 or 4 Rash: (2) 4% Pruritus: 0 Urticaria: 0 Blister: 0	All patients in sequenced treatment All grades: Rash: (3) 9% Pruritus: (6) 18% Vitiligo: 0 Night sweats: 0 Grade 3 or 4 Rash: 0 Pruritus: 0 Vitiligo: 0 Night sweats: 0
YAMAZAKI et al, 2015 [44] Japan	NRCT, phase 2	20	62.5 (29–76)	IPI (administered intravenously every 3 weeks at a dose of 3 mg/kg)	Grade 1 or 2 Rash (7) 35 Pruritus (2) 10% Alopecia (1) 5%
YAMAZAKI^a et al, 2017 [58 Japan	NRCT, phase 1b	42	65 (39–89)	Pembrolizumab (administered intravenously at a dose of 2 mg/kg, every 3 weeks, during a 30-min period)	Grade 1 or 2 Pruritus: (6) 14.3% Maculopapular rash: (6) 14.3% Vitiligo (3) 7.1% Skin hypopigmentation: (2) 4.8% Dry skin (2) 4.8%
YAMAZAKI^b et al, 2017 [59] Japan	NRCT, phase 2	35	64 (28–79)	Nivolumab 2 mg/kg was given as an intravenous infusion every 3 weeks in each 6-week treatment cycle.	Any grade Leukoderma: (6) 17.1% Pruritus: (11) 31.4% Rash: (2) 5.7% Rash maculopapular: (2) 5.7% Seborrheic dermatitis: (2) 5.7% Skin hypopigmentation: (4) 11.4%
YAMAZAKI^c et al, 2017 [60] Multicentric	NRCT, phase 2	24	63 (26–81)	Nivolumab (at a dose of 3 mg/kg every 2 weeks)	Grade 1 or 2 Vitiligo: (9) 37.5% Pruritus (6) 25% Rash maculopapular: (3) 12.5%
ZIMMER^a et al, 2015 [45] Multicentric	NRCT, phase 2	103 Cutaneous melanoma (83) Mucosal melanoma (7) Melanoma of unknown Primary (13)	Cutaneous melanoma 63 (29–85) Mucosal melanoma 63 (33–37) Melanoma of unknown Primary 62 (40–77)	IPI was administered intravenously over 90 min at a dose of 3 mg/kg every 3 weeks for a total of four infusions.	Grade 1 or 2 Pruritus: (11) 11% Rash: (9) 9% Erythema multiforme: (4) 5% Hand-foot-syndrome: (1) 1% Grade 3 or 4 Pruritus: 0 Rash: 0 Erythema multiforme: 0 Hand-foot-syndrome: 0
ZIMMER^b et al, 2015 [46] Multicentric	NRCT, phase 3	53	67 (34–84)	IPI (3 mg/kg) in 3-week intervals, for four cycles.	All grades Rash: (3) 6% Pruritus: (5) 9% Erythema multiforme: (3) 6%	Grade 3 or 4 Rash: 0 Pruritus: 0 Erytema multiforme: 0

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AE(s) = adverse event(s); CNS = central nervous system; CTCAE = Common Terminology Criteria for Adverse Events; DTIC = dacarbazine; Group A-MD = multiple dose (up to 5 mg/kg); Group A-SD = single dose (up to 20 mg/kg); Group B = multiple dose (up to 10 mg/kg); ICC = investigator’s choice chemotherapy; FDA = Food and Drug Administration; IPI = Ipilimumab; irAE(s) = immune-related adverse event(s); kg = kilogram; m ² = square meters; MD = multiple dose; mg = milligram(s); min = minute(s); NRCT = non-randomized clinical trial; OS = Observational Study; RCT = randomized clinical trial; SD = single dose; USA = United States of America.

Results of the individual studies

Among the studies included, 21 of them evaluated patients with advanced melanoma [29,32–34,37,38,40,43,44,48,50,53,55–60,62–64], 11 evaluated patients with metastatic melanoma [27,28,30,31,35,36,39,45,46,52,65] and seven studies evaluated patients with either stage III or IV irresectable melanoma or stage III or IV melanoma resected [41,42,47,49,51,54,61]. Overall, 9,847 patients were evaluated, and the samples in the individual studies ranged from ten [39] to 1,019 patients [61]. One of the studies [65] considered the total number of AEs observed during the study period as representative of the sample, thus not having a sample per number of patients. The mean age of the study participants was 60 years.

Regarding the ICI classes, only the anti-PD-L1 class was not analyzed in the studies included in this review. However, 15 studies studies evaluated the anti-CTLA4 class [27–29,31,32,34,36,39,44–47,51–53] and eight evaluated the anti-PD-1 class [33,49,50,54,58–61]. Several studies assessed the combined treatment with ICIs [38,41,43,48,55–57,63–65], whereas other studies evaluated the treatment with ICIs in combination with or in comparison to chemotherapy [30,35,37,40,42,62].

As to anti-CTLA4 class, the drug tremelimumab was evaluated alone at doses of 3, 6, 10, or 15 mg/kg [28] and, in comparison with chemotherapy (dacarbazine) [35]. Ipilimumab monotherapy was evaluated at doses of 3, 10, and 20 mg/kg, and the 3 mg/kg and 10 mg/kg doses were compared with each other [27,29,31,32,34,39,44–47,51–53]. The effect of ipilimumab treatment was also assessed in combination with nivolumab [38,41,48,63–65] and pembrolizumab [55,57], in comparison to nivolumab [56] or pembrolizumab [43] treatment, and in combination with chemotherapy (dacarbazine or paclitaxel + carboplatin) [30,37]. One study [36] did not describe the administered ipilimumab dose. Dermatological toxicity was more frequently observed in patients who used ipilimumab than in those who used nivolumab or pembrolizumab and included mainly rash and pruritus. Moreover, when the administration of ipilimumab was investigated in combination with chemotherapy, the dermatological toxicity was high in the ipilimumab group [30,37].

Regarding the anti-PD-1 class, the drug nivolumab was evaluated as monotherapy at doses of 2 mg/kg and 3 mg/kg [50,54,59,60] and compared with chemotherapy [40,62]. Higher frequencies of the AEs were observed at higher doses. When compared with chemotherapy, it was observed that the group treated with nivolumab also had dermatological AEs more frequently than the chemotherapy group in both grades 1 and 2, and in grades 3 and 4. Pembrolizumab was evaluated as monotherapy at doses of 2, 10, and 200 mg [33,49,58,61] and compared with chemotherapy [42].

Among the studies that were evaluated, the most frequent dermatological toxicities were rash [27–33,35,37–48,51,53–57,59–65], pruritus [28–33,35–46,48–49,51,53–65], vitiligo [27,33,38,40–43,49,50,52,55,57–62], dry skin [42,58,62], erythema multiforme [45,46], and skin hypopigmentation [58,59].

Other dermatological toxicities were reported by the studies such as alopecia [44], blister [38], dermatitis [32], drug eruption [55], eczema [52], erythema nodosum [51], folliculitis [52], hand-foot syndrome [45], leukoderma [59],lichenoid exanthema [36], maculopapular exanthema [36], mucositis [52], pemphigoid lesion [55], photosensitivity reaction [36], pruritic eczema [36], pyoderma gangraenosum [36], rosacea [52], seborrheic dermatitis [59], syringometaplasia [52], Stevens-Johnson Syndrome [52], sever skin reactions; eczema, lichenoid or psoriasiform skin irritation [49], toxic skin eruption [51], urticaria [38], and xerosis [52], DRESS syndrome [36,55].

Rash

Rash grades 1 and 2 [35] was observed with the administration of tremelimumab. When compared to chemotherapy, the tremelimumab-group had a higher frequency of rash than the dacarbazine.

When ipilimumab was administered alone, grades 1 and 2 rash were developed. When ipilimumab was administered in combination with nivolumab [38,41,48,63–65] or in the combination ipilimumab plus pembrolizumab [55,57], patients developed all grades of rash. Maculopapular rash were also observed in patients using ipilimumab [48,51] and nivolumab [48,60,62,63]. Pruritic rash was also reported in patients using ipilimumab [51]. Studies evaluating monotherapy with nivolumab [50,54,59,60] showed grade 1 and 2 rash. However, the occurrence of grade 3 and 4 rash was less frequent [40,62].

Pruritus

Grades 1 and 2 of pruritus was observed when tremelimumab was evaluated alone [28,35], when ipilimumab was administered alone [27,29,31,32,34,39,44–47,51–53] or in combination with nivolumab [38,41,48,63–65] or pembrolizumab [55,57]. Monotherapy with nivolumab [50,54,59,60] or pembrolizumab [33,49,58,61] also showed grades 1 and 2 pruritus. Although less frequent, grade 3 and 4 pruritus were observed especially in the combination of nivolumab with ipilimumab [41,48,64], and in the combination of nivolumab with chemotherapy [30,40].

Vitiligo

Vitiligo was observed only with the administration of the anti-PD-1 class. Studies evaluating monotherapy with nivolumab and pembrolizumab showed the occurence of vitiligo grade 1 and 2 [33,49,58,61]. When in comparison with chemotherapy, the group treated with nivolumab or pembrolizumab experienced a higher frequency of vitiligo than the group undergoing chemotherapy [40,42].

Other toxicities

Dry skin grade 1 and 2 was observed in patients using pembrolizumab alone [58], and in patients who were treated with pembrolizumab or nivolumab in comparison with chemotherapy [42,62]. Higher frequency of dry skin was observed on the group treated with immunotherapy.

Skin hypopigmentation was observed in patients using pembrolizumab [58], ipilimumab [36], and nivolumab [59]. Some patients using ipilimumab had acneiform rash/eruption [36,52], erythema multiforme [45,46], and DRESS syndrome (Drug Rash with Eosophilia and Systemic Symptoms) [36,55].

Risk of bias among the studies

Among the clinical trials, 18 had low risk of bias [30,31,35,37,38,40,42,43,45–48,51,55,56,61,62,64], whereas 10 presented moderate risk of bias [27–29,33,41,44,58–60,63]. Domains related to the sample size and statistical analysis contributed to the classification of clinical trials as presenting moderate risk of bias. It was not possible to evaluate the representativeness of the sample size in multicenter studies [28,33,59,60,63]. Even among the studies conducted at a single center, the samples were small [29,41,44,58]. Moreover, it was not possible to verify whether the response rate was properly managed [28,29,33,44,60], or whether the samples were adequately analyzed [29,58]. In other studies, the statistical analysis of the data was not clearly described and was thus impossible to evaluate [27,41], the sample analysis was insufficient [44,60], and it was impossible to determine the suitability of the method for assessment of the condition [41] or the reliability of the condition measurement [27].

Among the observational studies, the risk of bias was considered low, moderate, and high in one [54], two [32,53], and eight studies [34,36,39,49,50,52,57,65], respectively. The studies were considered to have moderate risk of bias, when it was not possible to evaluate whether the sample represented the population or harm [32,53], or whether the statistical analysis of the data was performed adequately [53]. Among the studies with high risk of bias, most inconsistencies referred to the uncertain description of the response rate or lack of its management [34,36,39,49,50,52,57,65], unrepresentative and unstratified samples [34,39,49,50,52,57], lack of description of the statistical analyses [36], use of an unusual statistical analysis [39], or unclear adequacy of the statistical analysis [34].

The detailed evaluation of each study is presented in S3 File.

Synthesis of the results

Among the included 39 studies, 34 were grouped to perform a meta-analysis. Four studies were excluded, because they did not grade the AEs (n = 3) [36,37,64,65] or because the reported ipilimumab AEs were caused by combined administration with chemotherapy (n = 1) [30].

We analyzed the dermatological toxicities which have been reported by two or more studies: rash, pruritus, vitiligo, dry skin, and erythema multiforme. Despite two or more studies had reported skin hypopigmentation and DRESS syndrome, it was not possible to perform the meta-analysis for these toxicities because they were not graduated [36,59] or were reported in different grades [36,55]. The heterogeneity among the studies that evaluated grades 1 to 4 rash, grades 1 and 2 pruritus, and grades 1 and 2 vitiligo was high (rash grades 1 and 2—I² = 96.93%, p = 0.001, CI = 0.20–0.31; rash grades 3 and 4—I² = 79.68%, p = 0.001, CI = 0.01–0.02; pruritus grades 1 and 2—I² = 87.21%, p = 0.001, CI = 0.21–0.27; and vitiligo grades 1 and 2—I² = 88.37%, p = 0.001, CI = 0.07–0.13). Therefore, we opted to use random effect models for the statistical analysis. The heterogeneity could be explained by the high number of included studies (n = 39), observed by the between-study differences regarding proportion of events.

The results of the meta-analyses for grades 1 and 2 rash, pruritus, vitiligo, erythema multiforme, and dry skin are shown in Figs 2–6. The results of the meta-analysis for grades 3 and 4 rash outcomes and pruritus are shown in S1 and S2 Figs, respectively.

Fig 6 — Elaborated by the authors using JAMOVI^®. Legend: NIVO—Nivolumab, PEMBRO—Pembrolizumab.

The prevalence of grades 1 and 2 rash and grades 3 and 4 rash was 26% (Fig 2) and 2% (S1 Fig), respectively. The prevalence of grades 1 and 2 pruritus (Fig 3) and grades 3 and 4 pruritus were 25% and 1%, respectively (S2 Fig). However, the prevalence of grades 1 and 2 vitiligo was 10% (Fig 4). We could not evaluate the prevalence of grades 3 and 4 vitiligo because only one study [27] described this event. The prevalence of erythema multiforme grade 1 and 2 was 4% (Fig 5), and dry skin grade 1 and 2 was 4% (Fig 6). The studies did not describe higher grades of erythema multiforme or dry skin. For this reason, we could not evaluate the prevalence of these events in grades 3 and 4.

Fig 4 — Elaborated by the authors using JAMOVI^®. Legend: IPI—Ipilimumab, NIVO—Nivolumab, PEMBRO—Pembrolizumab.

Fig 5 — Elaborated by the authors using JAMOVI^®. Legend: IPI—Ipilimumab.

Discussion

Cutaneous AEs are often the first toxicities to occur with the use of ICIs. Despite being self-limited, these toxicities may lead to ICI dose interruption or treatment discontinuation [66]. Dermatological toxicities might be mediated by a shared antigen which is coexpressed by the tumor cells and dermoepidermal junction [10,12].

Furthermore, cutaneous AEs are related to T-cell activation mediated by the blockade of PD-1 (or the PD-L1 ligand) and CTLA-4 receptors as well as the cross-reactivity between T cells directed against a tumor and T cells directed against normal tissue antigens [67]. Several hypotheses investigate factors that influence the risk of irAE development, including genetic factors, cytokines, and the composition of the patient’s gastrointestinal microbiological flora [11].

The most frequent cutaneous AEs identified in this meta-analysis were grade 1 and 2 pruritus (24%), grade 1 and 2 rash (21%), grade 1 and 2 vitiligo (10%), grade 1 and 2 erythema multiforme (4%), and grade 1 and 2 dry skin. There was a higher prevalence of grades 1 and 2 compared to grades 3 and 4 of these AEs. According to Postow [68], approximately 50% of the patients treated with ICIs, mainly ipilimumab, may develop pruritus and rash. Pruritus is considered the most frequent AE reported by patients treated with ICIs. The prevalence of pruritus is high with ipilimumab administered alone or in combination with other ICIs and, usually appears concomitantly with rash; however, pruritus may also precede the rash or even appear with intact skin [67,69]. Like pruritus, rash is also one of the most frequently observed AEs in patients treated with ICIs [69] and, often start after few treatment cyles occuring mainly on the trunk and extremities [70].

Vitiligo is a commonly observed irAE with ICI treatment in patients with melanoma and it is more frequently associated with the use of PD-1 inhibitors (nivolumab and pembrolizumab) compared to the use of CTLA-4 inhibitors (ipilimumab) [71]. In this review, among the studies that identified vitiligo as an irAE [27,33,40–43,49,50,52,57,58,60–62], the majority of them evaluated patients treated with anti-PD-1 as a monotherapy or in combination therapy [33,40–43,49,50,57,58,60–62]. The development of vitiligo in patients treated with anti-PD-1 is caused by the activated anti-melanoma immunity that targets both malignant and healthy melanocytes [72,73] and, its occurrence has been associated with an objective response and a prolonged overall survival [12]. Studies have shown that not only vitiligo, but also rash has been associated with clinical benefits in patients treated with nivolumab [74].

Erythema multiforme (EM) is not a very commom AE observed in patients undergoing immunotherapy. However, there are some case reports showing the development of EM-related to the administration of nivolumab and ipilimumab [75,76] that required immunotherapy discontinuation, and corticosteroid treatment. Nevertheless, the studies in this review reported grade 1 and 2 EM which did not lead to treatment discontinuation. Meantime, dry skin is a commom AE related to both chemotherapy and immunotherapy. It is important to educate patients on the use of moisturizers to prevent itching.

The manifestation of cutaneous irAEs occurs at the beginning of treatment, typically 3–6 weeks after treatment initiation [77]. Most grade 3 or 4 irAEs occur later, 12–14 weeks after the beginning of treatment [78]. In this meta-analysis, the prevalence of grade 3 or 4 irAEs was lower compared to grade 1 or 2 irAEs [27,29–31,33,35,38,40,41,43,47,48,51–57,61–64]; however, more than half of the studies identified grade 3 or 4 AEs.

Most studies that presented grade 3 or 4 irAEs (n = 15) evaluated the use of ipilimumab alone [27,29,31,43,47,48,51–53] or in combination therapy [30,38,41,56,63,64]. Ipilimumab has a more unfavorable toxicity profile than PD-1 inhibitors. Regarding grade 3 or 4 AEs, their incidence is 20%–30% in patients receiving ipilimumab and 10%–15% in patients receiving PD-1 inhibitors. The combination of ipilimumab and PD-1 inhibitors increases the incidence of grades 3 and 4 AEs to 55% [79].

Combined anti-CTLA-4 and anti-PD-1 therapy is associated with the development of more frequent cutaneous irAEs of greater severity with an earlier onset than monotherapy with ICIs [60]. Combination treatment with nivolumab and ipilimumab reportedly exacerbates their AEs and triggers high rates of grades 3 and 4 AEs. As a result, patients may repeatedly seek emergency care and may need hospitalizations and systemic immunosuppression. Further, the combination treatment has a toxicological profile that combine the side effects of both agents [63–65]. Although this combination is effective for cancer treatment, the high irEA rates are concerning [67].

Therefore, the management of adverse events requires early recognition, in addition to monitoring and classifying the grade of toxicity. The early identification of these events is critical to define the most appropriate intervention, such as treatment with the use of corticosteroids, temporary or permanent interruption of the use of ICI [80].

High-degree AEs may be potentially fatal; thus, patients should be carefully evaluated for symptoms consistent with Stevens-Johnson syndrome, pemphigus or toxic epidermal necrolysis [81]. In our review, one study identified Stevens-Johnson syndrome [52], classified as grade 4, affecting only one patient. Pemphigoid lesion grade 4 was also reported by one study [55], affecting only one patient. Though was not possible to perceive wheter these toxicities led to treatment discontinuation. However, toxic epidermal necrolysis was not listed in any of the studies. Both events are considered dermatological emergencies with high morbidity power which require an immediate intervention, hospitalization, and treatment discontinuation [82].

The frequency of irAEs increases with treatment exposure and requires long-term monitoring. Patients receiving PD-1 inhibitors may present with cutaneous AEs up to one year after the initiation of treatment [83]. Thus, follow-up periods longer than 12 months would be ideal to identify the incidence of irAEs. Overall 14 studies included in our review presented follow-up periods ranging from 1 to 5 years, which is considered an adequate time for the identification of irAEs [30,35,38,39,44,47,48,51,55,56,60–63].

Further, authors did not always report the irAEs in the most appropriate manner, since important information such as the classification [36,65] and type of scales used to classify the AEs [27,36,65] was often not reported.

A positive aspect of the irAE report was the use of the Commom Toxicity Criteria for Adverse Events (CTC-AE) scale [28–35,37–64] to classify and grade irAEs by most of the studies included in this review. The CTC-AE scale was developed to report AEs manifested by patients participating in oncological clinical trials [84]. The use of the same scale by most of the studies allowed the standardization of the irAEs reported in this review. However, Spain & Larkin [79] point out that even though the CTC-AE scale is a good scale that can also be used in clinical practice, it may lead researchers and professionals to underestimate some of the irAEs, such as pituitary gland dysfunction, because it is a scale created for a pre-immunotherapy time.

Other dermatological manifestations were identified in the studies included in this review such as maculopapular exanthema, erythema multiforme, dermatitis, acneiform rash, lichenoid exanthema, folliculitis, rosacea, eczema, leukoderma, seborrheic dermatitis, and alopecia. The majority of them were classified as grade 1 and 2.

Limitations

The heterogeneity of the samples, lack of grading of the AEs in some studies, and unknown time of onset of the AEs may have impaired the analysis of the outcomes. It was not possible to identify subsets of patients with high possibility of displaying cutaneous side effects. Thus, future studies should classify and grade the immunomediated AEs accurately, present the time of onset of the manifested AEs, and report the management and reversibility of the described AEs.

Conclusion

The results of this review and meta-analysis show that the most prevalent irAEs are pruritus and rash. Even though mild and moderate irAEs were reported more frequently than severe irAEs in the included studies, there was also a significant representation of more severe AEs. Grade 3 or 4 irAEs have been associated with the use of ipilimumab. Although it is possible to manage these AEs in most cases, early identification plays a key role in the prevention of severe cases, avoiding treatment interruption.

Supporting information

S1 Checklist. PRISMA checklist.

(DOC)

Click here for additional data file.^{(64.5KB, doc)}

S1 Fig. Meta-analysis of grade 3 or 4 rash outcomes.

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Click here for additional data file.^{(211KB, tif)}

S2 Fig. Meta-analysis of grade 3 or 4 pruritus outcomes.

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Click here for additional data file.^{(131.2KB, tif)}

S1 File. Search Strategy performed in the databases CINAHL, COCHRANE CENTRAL, LILACS, LIVIVO, PUBMED, SCOPUS, WEB OF SCIENCE, GOOGLE SCHOLAR, and OPENGRAY.

(DOCX)

Click here for additional data file.^{(20.9KB, docx)}

S2 File. Articles excluded after reading the full text (phase 2).

(DOCX)

Click here for additional data file.^{(79.9KB, docx)}

S3 File. Risk of bias in the included studies.

(DOCX)

Click here for additional data file.^{(26.1KB, docx)}

S1 Protocol. PROSPERO protocol.

(PDF)

Click here for additional data file.^{(1.8MB, pdf)}

Data Availability

All relevant data are within the paper and its Supporting Information files.

Funding Statement

This work was funded by a grant from the National Council for Scientific and Technological Development (CNPq), Brazil to CIV (Grant no. 437802/2018-3). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

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PLoS One. doi: 10.1371/journal.pone.0255716.r001

Decision Letter 0

Gayle E Woloschak

13 Oct 2020

PONE-D-19-20870

Prevalence of dermatological toxicities in cancer patients undergoing immunotherapy: systematic review and meta-analysis

PLOS ONE

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One reviewer rejected this, the other suggested major revisions. In particular, comments were made about the need to update the literature, to take the entire literature in consideration when writing the document, and the need to correct grammatical errors. Please address these in a revision if it is possible.

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Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #1: Partly

Reviewer #2: Partly

**********

2. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: I Don't Know

Reviewer #2: Yes

**********

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Reviewer #1: No

Reviewer #2: Yes

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4. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #1: Yes

Reviewer #2: Yes

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5. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: This meta analysis of studies reported 2008-18 seeks to distill the cutaneous toxicities of ICI given alone or in combination. The review is reasonably comprehensive but spans both adjuvant and advanced disease studies of single agents and combinations, as utilized for the therapy of cutaneous melanoma. There has been an increasing literature related to the mechanism of ICI, and the immunological basis of autoimmune toxicities across a range of other organs that is not addressed in this work. Indeed, the dissection of cutaneous toxicities without prospective specification of whether dermatologic evaluations by specialists, or using biopsy pathology, is not addressed in these studies. The interpretation that rash, pruritis and vitiligo are induced by these agents (and other immunotherapies of melanoma) is not new, nor are new insights provided.

The paper is riddled with grammatical and spelling errors too numerous to recount.

Reviewer #2: Dear Editor,

Thank you for trusting me as a reviewer.

My comments are as follows:

Title

1. Make clear in the Title that the population was not “cancer” patients but “melanoma” patients.

Abstract:

1. The authors mention “To identify the prevalence of cutaneous toxicity in patients with melanoma on treatment with immune isolated checkpoint inhibitors, combined or associated with chemotherapy and/or radiotherapy.”

Did you consider checkpoint inhibitors as monotherapy AND combined with chemo and radiotherapy, or did you consider only the combinations? Please clarify.

Introduction

1. S64 : has -> have

2. S72: differente -> different

Material methods

1. PRISMA: OK

2. PROSPERO: OK

3. Inclusion και exclusion criteria: clear and analytic

4. Search strategy – study selection – data extraction: OK

5. S145: omit parenthesis

6. Risk of bias: ΟΚ

7. Summary and synthesis of the results: the authors mention the primary outcome and define it (159: «the frequence … ICI”), but in synthesis they do not mention how did they estimate the prevalence (is it pooled prevalence?). Furthermore they do not mention if they estimated confidence intervals, prevalence and CI, especially, in the cases of very low incidence (logit or double arcsine transformation method is preferable, Barendregt J et al. Meta-analysis of prevalence). In my view, even if it was not performed, it should be mentioned in the statistical analysis section.

8. Two major issues:

• Initially, the authors mention they estimated heterogeneity (I2) and based on this the used the corresponding models (random ή fixed), but they do not analyze the reasons of heterogeneity, not even in the section they present their results (s302 – 308). In addition they do not mention if there were subgroup analyses for the investigation of heterogeneity, especially when found very high (Ι2 = 88%. Ι2= 84%). Even if not performed (or when performed did not change the result?), it would be interesting to know which was the conclusion.

• There are no comments or test of publication bias (no funnel plot). This must be included.

Results

1. Flow chart – study characteristics: OK

2. S224-5: reason for not analyzed the antiPDL1. It is fine that the authors mention that they did not study this class of drugs, but I would like them to give reasons for this decision.

3. Graphic s4. In the text the authors mention that pruritus 3-4 is 1% and eruption 3-4 is 1% with reference to s4. However, in s4 the authors have included only pruritus.

4. Graphic s4. Which was the methodology the authors used for the investigation of heterogeneity among the diverse studies for pruritus and the eruption? Was it random or fixed? Please clarify. If they did so, exclusively for pruritus, they must change s315.

5. S394 differente -> different

General comments

1. Page 13,14 (s 230 – 263) the authors give the rates of AE only as a range. The latter was not pre-defined in the statistical analysis section. I presume these are the CIs, but I consider they should be defined for clarification reasons.

2. In addition, they give just the range, without a certain rate in conjunction with the range.

3. In the end of each paragraph (e.g. 234-235 or 246-247 or 257-259, there are no rates and CIs, but only their conclusions. I recommend to include them, too.

Sincerely,

Zoe Apalla

**********

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Reviewer #1: No

Reviewer #2: Yes: Zoe Apalla

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PLoS One. 2021 Aug 6;16(8):e0255716. doi: 10.1371/journal.pone.0255716.r002

Author response to Decision Letter 0

3 Nov 2020

October 14th, 2020

Gayle E. Woloschak, PhD

Academic Editor

PLOS ONE

Dear Dr. Woloschak,

Thank you for the opportunity to revise and improve the manuscript PONE-D-19-20870 entitled " Prevalence of dermatological toxicities in cancer patients undergoing immunotherapy: systematic review and meta-analysis".

We would like to thank the reviewers for their valuable comments and suggestions. We have addressed all points raised by the reviewers and made revisions accordingly. Below, we have listed the reviewer’s comments and our responses. The changes have been highlighted in the revised version and marked in red font.

Responses to the Reviewers

Title

1. Make clear in the Title that the population was not “cancer” patients but “melanoma” patients.

Response: We replaced the word “cancer” for “melanoma”. The modified title is “Prevalence of dermatological toxicities in patients with melanoma undergoing immunotherapy: systematic review and meta-analysis”

Abstract:

Did you consider checkpoint inhibitors as monotherapy AND combined with chemo and radiotherapy, or did you consider only the combinations? Please clarify.

Response: It was clarified in the abstract and at the end of introduction.

"To identify the prevalence of cutaneous toxicity in patients with melanoma on treatment with immune checkpoint inhibitors as monotherapy and/or, combined with chemotherapy and/or radiotherapy" (page 2, line 38; page 4, line 82).

Introduction

1. S64 : has -> have

2. S72: differente -> different

Response: Thank you. We replaced the words.

Material methods

1. S145: omit parenthesis

Response: Done.

2. Summary and synthesis of the results: the authors mention the primary outcome and define it (159: «the frequence … ICI”), but in synthesis they do not mention how did they estimate the prevalence (is it pooled prevalence?). Furthermore, they do not mention if they estimated confidence intervals, prevalence and CI, especially, in the cases of very low incidence (logit or double arcsine transformation method is preferable, Barendregt J et al. Meta-analysis of prevalence). In my view, even if it was not performed, it should be mentioned in the statistical analysis section.

Response: Thank you for this appointment. The prevalence was estimated by the number of events out of the total of the sample. We add this information in the statistical analysis section (page 7, line 164).

3. Two major issues:

• Initially, the authors mention they estimated heterogeneity (I2) and based on this the used the corresponding models (random ή fixed), but they do not analyze the reasons of heterogeneity, not even in the section they present their results (s302 – 308). In addition, they do not mention if there were subgroup analyses for the investigation of heterogeneity, especially when found very high (Ι2 = 88%. Ι2= 84%). Even if not performed (or when performed did not change the result?), it would be interesting to know which was the conclusion.

Response: We added more information to the Method Section (page 7, lines 170-172). In the synthesis of the results, we add more details to the outcomes, such as the p value and CI for each subgroup meta-analysis (page 31, lines 317-323).

• There are no comments or test of publication bias (no funnel plot). This must be included.

Response: We performed the funnel plot and doi plot for each outcome. However, Furuya-kanamori et al (2018) recommend that funnel plot should not be considered, since in prevalence studies the graphic results could be noninterpretability. Based on this paper, we did not presented the funnel plot and doi plot. We added this information in the method section (page 7, lines 170 -172).

Results

1. S224-5: reason for not analyzed the antiPDL1. It is fine that the authors mention that they did not study this class of drugs, but I would like them to give reasons for this decision.

Response: Some studies which evaluated anti-PDL1 drugs were identified in the database search. However, they were excluded on phase 2 for the following reasons (as mentioned in the Appendix 2 - S2 file): absence of dermatological toxicity, complementary studies with duplicated data, data extraction not possible and, other types of cancer.

2. Graphic s4. In the text the authors mention that pruritus 3-4 is 1% and eruption 3-4 is 1% with reference to s4. However, in s4 the authors have included only pruritus.

Response: We replaced the S4 figure which now presents the results for the rash grade 3-4.

3. Graphic s4. Which was the methodology the authors used for the investigation of heterogeneity among the diverse studies for pruritus and the eruption? Was it random or fixed? Please clarify. If they did so, exclusively for pruritus, they must change s315.

Response: Thank you for this important comment about the meta-analysis effect. We used only random effect and we changed the figure.

4. S394 differente -> different

Response: Done.

General comments

Response: The range are not based on the CIs, it is the frequency of the event, i.e. the percentage of the events out of the total n.

2. In addition, they give just the range, without a certain rate in conjunction with the range.

Response: As those symptoms were secondary outcomes in most individual studies, it was only possible to extract the percentage of the number of events of the AE.

3. In the end of each paragraph (e.g. 234-235 or 246-247 or 257-259, there are no rates and CIs, but only their conclusions. I recommend to include them, too.

Response: We included all the rates in the conclusion sentence made in each paragraph (page 13, lines 226-228; page 14, lines 245-248; page 14, lines 259-271; page 15, lines 276-277).

Attachment

Submitted filename: Response to reviewers PONE-D-19-20870.docx

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PLoS One. doi: 10.1371/journal.pone.0255716.r003

Decision Letter 1

Gayle E Woloschak

13 Jan 2021

PONE-D-19-20870R1

Prevalence of dermatological toxicities in patients with melanoma undergoing immunotherapy: systematic review and meta-analysis

PLOS ONE

Dear Dr. Vasques:

One reviewer suggested revisions, the other had no changes. Please address changes in a revision.

Please submit your revised manuscript by Feb 27 2021 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org. When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file.

Please include the following items when submitting your revised manuscript:

A rebuttal letter that responds to each point raised by the academic editor and reviewer(s). You should upload this letter as a separate file labeled 'Response to Reviewers'.
A marked-up copy of your manuscript that highlights changes made to the original version. You should upload this as a separate file labeled 'Revised Manuscript with Track Changes'.
An unmarked version of your revised paper without tracked changes. You should upload this as a separate file labeled 'Manuscript'.

We look forward to receiving your revised manuscript.

Kind regards,

Gayle E. Woloschak, PhD

Academic Editor

PLOS ONE

Additional Editor Comments (if provided):

One reviewer had major revisions, the other had no changes. Please address concerns in a revision.

[Note: HTML markup is below. Please do not edit.]

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation.

Reviewer #2: All comments have been addressed

Reviewer #3: (No Response)

**********

2. Is the manuscript technically sound, and do the data support the conclusions?

Reviewer #2: Yes

Reviewer #3: Partly

**********

3. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #2: Yes

Reviewer #3: I Don't Know

**********

4. Have the authors made all data underlying the findings in their manuscript fully available?

Reviewer #2: Yes

Reviewer #3: Yes

**********

5. Is the manuscript presented in an intelligible fashion and written in standard English?

Reviewer #2: Yes

Reviewer #3: No

**********

6. Review Comments to the Author

Reviewer #2: (No Response)

Reviewer #3: Overview: Important meta-analysis on a very common toxicity seen with ICIs. However I have some concerns about the way the information is presented. It reads a bit confusing/complicated. Another general important concept to address is WHY cutaneous toxicity in melanoma patients getting ICI is of specific interest. Notably vitiligo. Arguably the rash and vitiligo are a type of on target tox since melanoma starts as cancer of skin and attach of melanocytes suggests on target mechanism. Further vitiligo has correlated with response/survival in melanoma. In addition, similar to endocrinopathies, cutaneous tox is one of the irAEs that you can often treat through and not hold treatment but just manage symptomatically - unless progresses to SJS or TEN. Though not included in the meta-analysis I would add a paragraph just listing what has been reported in the literature when it comes to types of rashes (maculo-papular, psoriatic like, lichen planus, pemphigous etc).

Abstract:

Page 2 Line 45 - The first thing that jumped out to be was that the overall prevalence of pruritis (17%) and rash (12%) seem VERY low. I think there may be issue here with how this was arrived at. If you go to the the table 2, any grade or grade 1-2 are often higher than this. For example in your TABLE when listing reference 53 which is LONG et al JAMA Oncology 2017 if you go to the original text there is a "skin tox" listed as irAE which needs to be included and then your 11% would be more like 50%+. Further unsure why here just selected the non-TBP group.

Introduction:

Page 3 Line 63. Would reword sentence to read "The side effects related to ICIs are labeled as immune related adverse events (irAEs) and are thought to be related to [insert mechanism hypothesis]. Then would add something like "Though one can see irAes involving all body systems, cutaneous toxicity is of particular interest".

Page 3 Like 69: Would expand this to address what the cost is related to.

Eligibility

Page 4 Line 93: Would remind readers that this is MELANOMA patients.

Study Selection

Page 6 Line 125: Would replace argumentation with discussion

Comment on Statistics Methods/Synthesis/Results: I am not a statistician but this reads very confusing to me. Should somehow be simplified.

Table 1 and 2: This needs to be simplified. There is redundancy in how reported and too many words. You could consolidate to one table with columns listing Study Author and Year / Study Design [also include line of therapy here] / Drugs tested / Dermatologic Toxicities. Purpose of this paper is to highlight derm tox, other info not needed. Also I think the percentages of derm toxicities for some of the studies is not correct. See above concern about study [53].

Discussion

Page 32 Lines 322-329. This is contradictory. Say mechanism unknown but then list a mechanism. Would rephrase.

Overall would reword discussion. It is currently a repeat of what is already noted. Would comment on what is mentioned above in overview section.

**********

7. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.

Reviewer #2: Yes: Zoe Apalla

Reviewer #3: No

PLoS One. 2021 Aug 6;16(8):e0255716. doi: 10.1371/journal.pone.0255716.r004

Author response to Decision Letter 1

18 Mar 2021

Gayle E. Woloschak, PhD

Academic Editor

PLOS ONE

Dear Dr. Woloschak,

Thank you for the opportunity to revise and improve the manuscript PONE-D-19-20870R1 entitled " Prevalence of dermatological toxicities in cancer patients undergoing immunotherapy: systematic review and meta-analysis".

Responses to the Reviewers

Reviewer #3:

Overview: Important meta-analysis on a very common toxicity seen with ICIs. However I have some concerns about the way the information is presented. It reads a bit confusing/complicated. Another general important concept to address is WHY cutaneous toxicity in melanoma patients getting ICI is of specific interest. Notably vitiligo. Arguably the rash and vitiligo are a type of on target tox since melanoma starts as cancer of skin and attach of melanocytes suggests on target mechanism. Further vitiligo has correlated with response/survival in melanoma. In addition, similar to endocrinopathies, cutaneous tox is one of the irAEs that you can often treat through and not hold treatment but just manage symptomatically - unless progresses to SJS or TEN. Though not included in the meta-analysis I would add a paragraph just listing what has been reported in the literature when it comes to types of rashes (maculo-papular, psoriatic like, lichen planus, pemphigous etc).

Response: As suggested by the reviewer, we added on discussion section a paragraph listing other dermatological toxicities mentioned by the studies included in the review. “Other dermatological manifestations were identified in the studies included in this review such as maculopapular exanthema, erythema multiforme, dermatitis, acneiform rash, lichenoid exanthema, folliculitis, rosacea, eczema, leukoderma, seborrheic dermatitis, and alopecia. The majority of them were classified as grade 1 and 2. Although it is possible to manage these AEs in most cases, early identification plays a key role in the prevention of severe cases, avoiding treatment interruption.” (page 32, lines 408-413)

Abstract:

Response: We decided not to present the overall prevalence for pruritus and rash. These signs/symptoms are adverse events that evolve gradually, for example, the patient that presents pruritus classified as grade 1 and 2 in the beginning of the treatment can evolve to grade 3 and 4 later. Thus, when calculating the overall prevalence we may be counting the same patient twice. For this reason, we decided to present only the results of the subgroup analysis grade 1 and 2 and, grade 3 and 4 for both pruritus and rash.

The modified sentence on the abstract is : “The results suggest that the most prevalent side effect was grade 1 and 2 pruritus (24%), followed by grade 1 and 2 rash (21%) and grade 1 and 2 vitiligo (10%).” (page 2, lines 44-46)

Regarding the reference n. 53 (Long et al, 2017), which now is n. 54 due to the insertion of a new reference in the introduction, we inform that we did not selected one specific group. The data from both non-TBP group and TBP group have already been described in table. As suggested by the reviewer, we included the data related to “skin tox” in table 1.

Introduction:

Response: We inserted the reviewer’s suggestion. The modified sentence is presented above.

“(…) The side effects related to ICIs are labeled as immune-related adverse events (irAEs) and are thought to be related to the inflammatory response caused in several organs due to the stimulation of the immune system, especially of T cells [9,10, 11]. Though one can see irAEs involving all body systems, cutaneous toxicity is of particular interest.” (page 3, lines 63-67)

Page 3 Like 69: Would expand this to address what the cost is related to.

Response: We included the information as suggested.

“The cost associated with the management of dermatological toxicity in patients with metastatic melanoma reaches US $ 21,726.00 per month, which represent the total adjudicated amount paid to all providers for inpatient and outpatient services and drugs [14].” (page 4, lines 77-79)

Eligibility

Page 4 Line 93: Would remind readers that this is MELANOMA patients.

Response: We included the word melanoma.

“We included clinical trials (randomized and non-randomized) and observational studies that evaluated melanoma cancer patients undergoing treatment with a single ICI, a combination of ICIs, or a combination of an ICI with chemotherapy and/or radiotherapy and that described the prevalence of dermatological toxicity.” (page 5, lines 105)

Study Selection

Page 6 Line 125: Would replace argumentation with discussion

Response: We replaced the word argumentation for discussion.

“(…) Any disagreements in the first or second phase were resolved by discussion until an agreement was reached between the two authors.(…)” (page 6, line 136)

Response: We consolidated the tables. Table 2 now is presented as table 1 in which we inserted the columns author/year/contry and, study design that were originally from table 1. All other data have not been changed. Regarding the study mentioned (reference n. 53, that now is 54 because of the insertion of one reference in the introduction), the percentages are correct. We inserted only the acronymun TBP (treatment beyond progression) and non-TBP to be the same as described by the author in the article, but all the data about non-TBP and TBP groups had already been described since the first version of the manuscript. (page 13)

STUDY CHARACTERISTICS SAMPLE CHARACTERISTICS EXPOSURE CHARACTERISTICS OUTCOME CHARACTERISTICS

Author, Year

Country Study design Sample size (n) Age in years (mean and range) Drug (dose and schedule) Duration of treatment Follow-up Dermatological toxicities (n) % Main Conclusions

LONGa et al, 2017 [54]

Australia Retrospective OS 306

Non-beyond

progression

(221)

Beyond

progression

(85)

62 (18-90) Nivolumab (3mg/kg every 2 weeks) Until progression or unacceptable toxic effects. Not described

Non-treatment beyond

Progression (Non-TBP)

Any Grade

Skin adverse event: (58) 26%

Pruritus: (25) 11%

Rash: (23) 10%

Grade 3 or 4

Skin adverse event: (2) 1%

Pruritus: (1) <1%

Rash: 0 Treatment Beyond

Progression (TBP)

Any Grade

Skin adverse event: (43) 51%

Pruritus: (23) 27%

Rash: (23) 27%

Grade 3 or 4

Skin adverse event: (1) 1%

Pruritus: 0

Rash: 0 Patients treated beyond

their first disease progression can experience a tumor response with continued nivolumab treatment, with a safety profile consistent with that observed in patients who did not receive further treatment.

Discussion

Page 32 Lines 322-329. This is contradictory. Say mechanism unknown but then list a mechanism. Would rephrase.

Response: We rewrote the sentence. The modified sentence is “Cutaneous AEs are the first toxicities to occur with the use of ICIs. Despite being self-limited, these toxicities may lead to ICI dose reduction and treatment discontinuation [66]. Dermatological toxicities might be mediated by a shared antigen which is coexpressed by the tumor cells and dermoepidermal junction [10, 12].”

Overall would reword discussion. It is currently a repeat of what is already noted. Would comment on what is mentioned above in overview section.

Response: We reworded many aspects of the discussion in order to address what was mentioned in the overview section. All the changes we made are highlighted in red font.

Attachment

Submitted filename: 16 03 2020 Response to reviewers PONE-D-19-20870.docx

Click here for additional data file.^{(29.8KB, docx)}

PLoS One. doi: 10.1371/journal.pone.0255716.r005

Decision Letter 2

Gayle E Woloschak

16 Apr 2021

PONE-D-19-20870R2

Prevalence of dermatological toxicities in patients with melanoma undergoing immunotherapy: systematic review and meta-analysis

PLOS ONE

Dear Dr. Vasques:

The reviewers considered that changes made were not yet sufficient for the work.

Please submit your revised manuscript by May 31 2021 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org. When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file.

Please include the following items when submitting your revised manuscript:

A rebuttal letter that responds to each point raised by the academic editor and reviewer(s). You should upload this letter as a separate file labeled 'Response to Reviewers'.
A marked-up copy of your manuscript that highlights changes made to the original version. You should upload this as a separate file labeled 'Revised Manuscript with Track Changes'.
An unmarked version of your revised paper without tracked changes. You should upload this as a separate file labeled 'Manuscript'.

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We look forward to receiving your revised manuscript.

Kind regards,

Gayle E. Woloschak, PhD

Academic Editor

PLOS ONE

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Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

Reviewer #3: (No Response)

**********

2. Is the manuscript technically sound, and do the data support the conclusions?

Reviewer #3: Yes

**********

3. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #3: N/A

**********

4. Have the authors made all data underlying the findings in their manuscript fully available?

Reviewer #3: Yes

**********

5. Is the manuscript presented in an intelligible fashion and written in standard English?

Reviewer #3: Yes

**********

6. Review Comments to the Author

Reviewer #3: I still think you miss the opportunity to make this a more complete meta-analysis of dermatologic toxicities. As it stand right now it is mostly a summary of the incidence of "rash" "pruritis" and "vitiligo". Though as you can see a number of studies are more detailed in their descriptions. You hit on this in the conclusion a bit but the majority of text just summarizes incidence of "rash" and "pruritis" which is very common and actually in clinical practice not always clinically significant. It is the more specific toxicities such as pemphigus, EN, etc that you actually hold or stop drug.

I would maybe like to see the paper organized by type of skin toxicity as opposed to results of individual studies. A number of the studies detail other more clinical significant cutaneous toxicities. The Table is still a bit long and too detailed. Would remove the column on duration of treatment as well as main conclusion (purpose of paper is not to educate on outcomes of the studies as pertains to cancer effect).

**********

7. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

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Reviewer #3: No

PLoS One. 2021 Aug 6;16(8):e0255716. doi: 10.1371/journal.pone.0255716.r006

Author response to Decision Letter 2

28 May 2021

May 28th, 2021

Gayle E. Woloschak, PhD

Academic Editor

PLOS ONE

Dear Dr. Woloschak,

Responses to the Reviewers

Reviewer #3:

I still think you miss the opportunity to make this a more complete meta-analysis of dermatologic toxicities. As it stand right now it is mostly a summary of the incidence of "rash" "pruritis" and "vitiligo". Though as you can see a number of studies are more detailed in their descriptions. You hit on this in the conclusion a bit but the majority of text just summarizes incidence of "rash" and "pruritis" which is very common and actually in clinical practice not always clinically significant. It is the more specific toxicities such as pemphigus, EN, etc that you actually hold or stop drug.

Response: As suggested by the reviewer, we looked again at the studies included in this review to bring out the dermatological toxicities in more detail, which can be seen in Table 1 (page 10-20), and in the results section (pages 22 -24, lines 247 - 317).

We identifiy that erythema multiforme, skin hypopigmentation, dry skin and DRESS syndrome were also reported by two or more studies. So we reported this in the result section (pages 22 -24, lines 247 - 317). For these reason, we rerun the meta-analysis for rash, pruritus and vitiligo, and we run the meta-analysis for erythema multiforme and dry skin, now on Jamovi software (page 25-26, lines 349 - 358; 376-390). It was not possible to run the meta-analysis for skin hypopigmentation because the studies did not classified this toxicity. Among the studies that reported DRESS syndrome, one reported the toxicity as grade 1and 2, and the other one as grade 3 and 4, which made impossible to perform the meta-analysis.

We also inserted a paragraph on discussion regard the inclusion of erythema multiforme and dry skin meta-analysis: “Erythema multiforme (EM) is not a very commom AE observed in patients undergoing immunotherapy. However, there are some case reports showing the development of EM-related to the administration of nivolumab and ipilimumab [75, 76] that required immunotherapy discontinuation, and corticosteroid treatment. Nevertheless, the studies in this review reported grade 1 and 2 EM which did not lead to treatment discontinuation. Meantime, dry skin is a commom AE related to both chemotherapy and immunotherapy. It is important to educate patients on the use of moisturizers to prevent itching” (page 28, lines 427-433).

Regarding the more specific toxicities with clinical impact, only one case of pemphigus (long et al, 2017), Steve-Johnson syndrome (Dika et al., 2017), and EN (Ascierto et al., 2017) were reported by the studies, but the authors did not make clear if these toxicities led to treatment discontinuation. However, we had already included a paragraph in the discussion section reporting the data about Steve-Johnson syndrome identified in this review, and stating the importance of monitoring signs and symptoms indicative of Steve-Johnson syndrome and toxic epidermal necrolisis. Now, we included a sentence about the data we found about pemphigoid lesion (page 29, lines 463-465):

“High-degree AEs may be potentially fatal; thus, patients should be carefully evaluated for symptoms consistent with Stevens-Johnson syndrome, pemphigus or toxic epidermal necrolysis [81]. In our review, one study identified Stevens-Johnson syndrome [52], classified as grade 4, affecting only one patient. Pemphigoid lesion grade 4 was also reported by one study [55], affecting only one patient. Though was not possible to perceive wheter these toxicities led to treatment discontinuation. However, toxic epidermal necrolysis was not listed in any of the studies. Both events are considered dermatological emergencies with high morbidity power which require an immediate intervention, hospitalization, and treatment discontinuation [82].”

Reviewer #3:

Response: We are now presenting the results by type of skin toxicity (pages 22 -24, lines 247-317).

As suggested, we removed the column on duration of treatment and main conclusion from table 1.

Attachment

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PLoS One. doi: 10.1371/journal.pone.0255716.r007

Decision Letter 3

Gayle E Woloschak

2 Jul 2021

PONE-D-19-20870R3

Prevalence of dermatological toxicities in patients with melanoma undergoing immunotherapy: systematic review and meta-analysis

PLOS ONE

Dear Dr. Vasques:

Minor revisions have been proposed as suggested below.

Please submit your revised manuscript by Aug 16 2021 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org. When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file.

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We look forward to receiving your revised manuscript.

Kind regards,

Gayle E. Woloschak, PhD

Academic Editor

PLOS ONE

Journal Requirements:

Please review your reference list to ensure that it is complete and correct. If you have cited papers that have been retracted, please include the rationale for doing so in the manuscript text, or remove these references and replace them with relevant current references. Any changes to the reference list should be mentioned in the rebuttal letter that accompanies your revised manuscript. If you need to cite a retracted article, indicate the article’s retracted status in the References list and also include a citation and full reference for the retraction notice.

Additional Editor Comments (if provided):

Some minor revisions related to rewording should be done before the next revision.

[Note: HTML markup is below. Please do not edit.]

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

Reviewer #3: (No Response)

**********

2. Is the manuscript technically sound, and do the data support the conclusions?

Reviewer #3: Yes

**********

3. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #3: Yes

**********

4. Have the authors made all data underlying the findings in their manuscript fully available?

Reviewer #3: Yes

**********

5. Is the manuscript presented in an intelligible fashion and written in standard English?

Reviewer #3: Yes

**********

6. Review Comments to the Author

Reviewer #3: 1) Page 3 Line 55: Would reword - patients achieving responses vs delay of disease progression are two different outcomes. May say something like "Many patients have been living longer due to remarkable responses and delay of disease progression"

2) Page 3 Line 63: Would reword - "Although in many cancers one can see anti-tumor activity with ICIs and traditional chemotherapy, the types, mechanisms, and rates of side effects differ"

3) Page 4 Line 87: Would reword - This review is a comprehensive report on the prevalence of dermatological toxicity in patients ...

4) Table 1: I would still further simplify. Would remove the Duration of treatment, Follow up, and main conclusions since really just highlighting incidence of cutaneous irAE

5) Page 29 Line 329: Reword - Cutaneous AEs are often the first toxicities

6) Page 29 Line 330: Reword - ... these toxicities may lead to IDI dose interruption or treatment discontinuation (there really isn't dose reduction with ICIs)

7) Page 32 Line 410: Would take sentence that starts with "Although it is possible ... and make it last sentence of conclusion

8) Page 33 Line 424: Would remove sentence that starts with "Vitiligo" and "Regarding" Make conclusion one paragraph

**********

7. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.

Reviewer #3: No

PLoS One. 2021 Aug 6;16(8):e0255716. doi: 10.1371/journal.pone.0255716.r008

Author response to Decision Letter 3

14 Jul 2021

July 12th, 2021

Gayle E. Woloschak, PhD

Academic Editor

PLOS ONE

Dear Dr. Woloschak,

Responses to the Reviewers

Reviewer #3:

1) Page 3 Line 55: Would reword - patients achieving responses vs delay of disease progression are two different outcomes. May say something like "Many patients have been living longer due to remarkable responses and delay of disease progression"

Our response: We reworded the sentence as suggested by the reviewer: “Many patients have been living longer due to remarkable responses and delay of disease progression during ICI treatment [3].”

Reviewer #3:

2) Page 3 Line 63: Would reword - "Although in many cancers one can see anti-tumor activity with ICIs and traditional chemotherapy, the types, mechanisms, and rates of side effects differ"

Our response: We reworded the sentence as suggested by the reviewer: “Although in many cancers one can see anti-tumor activity with ICIs and traditional chemotherapy, the types, mechanisms, and rates of side effects differ”.

Reviewer #3:

3) Page 4 Line 87: Would reword - This review is a comprehensive report on the prevalence of dermatological toxicity in patients ...

Our response: As suggested by the reviewer, we reworded the sentence: “This review is a comprehensive report on the prevalence of dermatological toxicity in patients with melanoma using ICIs as monotherapy and/or in combination with chemotherapy and/or radiotherapy.”

Reviewer #3:

4) Table 1: I would still further simplify. Would remove the Duration of treatment, Follow up, and main conclusions since really just highlighting incidence of cutaneous irAE

Our response: We removed the follow-up column from table 1. The duration of treatment and main conclusion columns had already been removed on previous revision. The table 1 now presents the following data: author/year/country, study design, sample size, age, drug (dose and schedule) and dermatological toxicities.

Reviewer #3:

5) Page 29 Line 329: Reword - Cutaneous AEs are often the first toxicities

Our response: We reworded as suggested: “Cutaneous AEs are often the first toxicities to occur with the use of ICIs. (…)”

Reviewer #3:

6) Page 29 Line 330: Reword - ... these toxicities may lead to IDI dose interruption or treatment discontinuation (there really isn't dose reduction with ICIs)

Our response: As suggested by the reviewer, we reworded the sentence: “Despite being self-limited, these toxicities may lead to ICI dose interruption or treatment discontinuation.”

Reviewer #3:

7) Page 32 Line 410: Would take sentence that starts with "Although it is possible ... and make it last sentence of conclusion

Our response: Done.

Reviewer #3:

8) Page 33 Line 424: Would remove sentence that starts with "Vitiligo" and "Regarding" Make conclusion one paragraph

Our response: We removed the sentences as suggested by the reviewer, included the sentence as suggested by the reviewer’s comment #7, and made the conclusion one paragraph as follow: “The results of this review and meta-analysis show that the most prevalent irAEs are pruritus and rash. Even though mild and moderate irAEs were reported more frequently than severe irAEs in the included studies, there was also a significant representation of more severe AEs. Grade 3 or 4 irAEs have been associated with the use of ipilimumab. Although it is possible to manage these AEs in most cases, early identification plays a key role in the prevention of severe cases, avoiding treatment interruption.”

Attachment

Submitted filename: Response to reviewers PONE-D-19-20870 (2021 07 12).docx

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PLoS One. doi: 10.1371/journal.pone.0255716.r009

Decision Letter 4

Gayle E Woloschak

23 Jul 2021

Prevalence of dermatological toxicities in patients with melanoma undergoing immunotherapy: systematic review and meta-analysis

PONE-D-19-20870R4

Dear Dr. Vasques:

We’re pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it meets all outstanding technical requirements.

Within one week, you’ll receive an e-mail detailing the required amendments. When these have been addressed, you’ll receive a formal acceptance letter and your manuscript will be scheduled for publication.

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Kind regards,

Gayle E. Woloschak, PhD

Section Editor

PLOS ONE

Additional Editor Comments (optional):

Thank you for addressing concerns raised by the review.

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

Reviewer #3: All comments have been addressed

**********

2. Is the manuscript technically sound, and do the data support the conclusions?

Reviewer #3: Yes

**********

3. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #3: Yes

**********

4. Have the authors made all data underlying the findings in their manuscript fully available?

Reviewer #3: Yes

**********

5. Is the manuscript presented in an intelligible fashion and written in standard English?

Reviewer #3: Yes

**********

6. Review Comments to the Author

Reviewer #3: (No Response)

**********

7. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.

Reviewer #3: No

PLoS One. doi: 10.1371/journal.pone.0255716.r010

Acceptance letter

Gayle E Woloschak

29 Jul 2021

PONE-D-19-20870R4

Prevalence of dermatological toxicities in patients with melanoma undergoing immunotherapy: systematic review and meta-analysis

Dear Dr. Inocêncio Vasques:

I'm pleased to inform you that your manuscript has been deemed suitable for publication in PLOS ONE. Congratulations! Your manuscript is now with our production department.

If your institution or institutions have a press office, please let them know about your upcoming paper now to help maximize its impact. If they'll be preparing press materials, please inform our press team within the next 48 hours. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information please contact onepress@plos.org.

If we can help with anything else, please email us at plosone@plos.org.

Thank you for submitting your work to PLOS ONE and supporting open access.

Kind regards,

PLOS ONE Editorial Office Staff

on behalf of

Dr. Gayle E. Woloschak

Section Editor

PLOS ONE

Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

S1 Checklist. PRISMA checklist.

(DOC)

Click here for additional data file.^{(64.5KB, doc)}

S1 Fig. Meta-analysis of grade 3 or 4 rash outcomes.

(TIF)

Click here for additional data file.^{(211KB, tif)}

S2 Fig. Meta-analysis of grade 3 or 4 pruritus outcomes.

(TIF)

Click here for additional data file.^{(131.2KB, tif)}

S1 File. Search Strategy performed in the databases CINAHL, COCHRANE CENTRAL, LILACS, LIVIVO, PUBMED, SCOPUS, WEB OF SCIENCE, GOOGLE SCHOLAR, and OPENGRAY.

(DOCX)

Click here for additional data file.^{(20.9KB, docx)}

S2 File. Articles excluded after reading the full text (phase 2).

(DOCX)

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S3 File. Risk of bias in the included studies.

(DOCX)

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S1 Protocol. PROSPERO protocol.

(PDF)

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Attachment

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Submitted filename: 16 03 2020 Response to reviewers PONE-D-19-20870.docx

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Submitted filename: Response to reviewers PONE-D-19-20870 (2021 05 28).docx

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Submitted filename: Response to reviewers PONE-D-19-20870 (2021 07 12).docx

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Data Availability Statement

All relevant data are within the paper and its Supporting Information files.

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PERMALINK

Prevalence of dermatological toxicities in patients with melanoma undergoing immunotherapy: Systematic review and meta-analysis

Náthali Felícia Mineiro dos Santos Garrett

Ana Cristina Carvalho da Costa

Elaine Barros Ferreira

Giovanni Damiani

Paula Elaine Diniz dos Reis

Christiane Inocêncio Vasques

Roles

Abstract

Background

Objective

Materials and methods

Results

Conclusion

Introduction

Materials and methods

Protocol and registration

Eligibility criteria

Information sources

Study selection

Data collection process

Risk of bias in individual studies

Summary measures

Synthesis of the results

Results

Study selection

Fig 1. Flow diagram of the literature search and selection criteria.

Characteristics of the studies

Table 1. Studies included in the review according to methodological characteristics (n = 39).

Results of the individual studies

Rash

Pruritus

Vitiligo

Other toxicities

Risk of bias among the studies

Synthesis of the results

Fig 2. Meta-analysis of rash outcome grade 1 or 2.

Fig 6. Meta-analysis of dry skin outcome grade 1 or 2.

Fig 3. Meta-analysis of pruritus outcome grade 1 or 2.

Fig 4. Meta-analysis of vitiligo outcome grade 1 or 2.

Fig 5. Meta-analysis of erythema multiforme outcome grade 1 or 2.

Discussion

Limitations

Conclusion

Supporting information

Data Availability

Funding Statement

References

Decision Letter 0

Gayle E Woloschak

Roles

Author response to Decision Letter 0

Decision Letter 1

Gayle E Woloschak

Roles

Author response to Decision Letter 1

Decision Letter 2

Gayle E Woloschak

Roles

Author response to Decision Letter 2

Decision Letter 3

Gayle E Woloschak

Roles

Author response to Decision Letter 3

Decision Letter 4

Gayle E Woloschak

Roles

Acceptance letter

Gayle E Woloschak

Roles

Associated Data

Supplementary Materials

Data Availability Statement

ACTIONS

PERMALINK

RESOURCES

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