Dermatologic Toxicity Research Articles

KDR genetic predictor of toxicities induced by sorafenib and regorafenib.

No biomarkers are available to predict toxicities induced by VEGFR TKIs. This study aimed to identify markers of toxicities induced by these drugs using a discovery-validation approach. The discovery set included 140 sorafenib-treated cancer patients (TARGET study) genotyped for SNPs in 56 genes. The most significant SNPs associated with grade ≥2 hypertension, diarrhea, dermatologic toxicities, and composite toxicity (any one of the toxicities) were tested for association with grade ≥2 toxicity in a validation set of 201 sorafenib-treated patients (Alliance/CALGB 80802). The validated SNP was tested for association with grade ≥2 toxicity in 107 (LCCC 1029) and 82 (Italian cohort) regorafenib-treated patients. SNP-toxicity associations were evaluated using logistic regression, and a meta-analysis between the studies was performed by inverse variance. Variant rs4864950 in KDR increased the risk of grade ≥2 composite toxicity in TARGET, Alliance/CALGB 80802, and the Italian cohort (meta-analysis p = 6.79 × 10-4, OR = 2.01, 95% CI 1.34-3.01). We identified a predictor of toxicities induced by VEGFR TKIs. CLINICALTRIALS.GOV IDENTIFIER: NCT00073307 (TARGET), NCT01015833 (Alliance/CALGB 80802), and NCT01298570 (LCCC 1029).

Cutaneous Adverse Events Associated with Immune Checkpoint Inhibitors: A Review Article.

Immune checkpoint inhibitors (ICIs) have emerged as novel options that are effective in treating various cancers. They are monoclonal antibodies that target cytotoxic T-lymphocyte antigen 4 (CTLA-4), programmed cell death 1 (PD-1), and programmed cell death-ligand 1 (PD-L1). However, activation of the immune systems through ICIs may concomitantly trigger a constellation of immunologic symptoms and signs, termed immune-related adverse events (irAEs), with the skin being the most commonly involved organ. The dermatologic toxicities are observed in nearly half of the patients treated with ICIs, mainly in the form of maculopapular rash and pruritus. In the majority of cases, these cutaneous irAEs are self-limiting and manageable, and continuation of the ICIs is possible. This review provides an overview of variable ICI-mediated dermatologic reactions and describes the clinical and histopathologic presentation. Early and accurate diagnosis, recognition of severe toxicities, and appropriate management are key goals to achieve the most favorable outcomes and quality of life in cancer patients.

Dermatologist awareness of scalp cooling for chemotherapy-induced alopecia

Chemotherapy-induced alopecia (CIA) is a distressing consequence of chemotherapy, with up to 14% of patients at risk of rejecting curative cancer therapies because of the fear of hair loss.1 Although the senior authors (J.S. and K.L.) regularly care for patients with CIA upon completion of their cancer treatment, they rarely have the opportunity to counsel patients before chemotherapy induction. This is in contrast to dermatologists’ frequent involvement in preventing other dermatologic toxicities of anticancer therapies.

Tolerability of Eribulin and correlation between polymorphisms and neuropathy in an unselected population of female patients with metastatic breast cancer: results of the multicenter, single arm, phase IV PAINTER study

BackgroundMetastatic breast cancer (MBC) is an incurable disease and its treatment focuses on prolonging patients’ (pts) overall survival (OS) and improving their quality of life. Eribulin is a microtubule inhibitor that increases OS in pre-treated MBC pts. The most common adverse events (AEs) are asthenia, neutropenia and peripheral neuropathy (PN).MethodsPAINTER is a single arm, phase IV study, aimed at evaluating the tolerability of eribulin in MBC pts. Secondary objectives were the description of treatment efficacy and safety, the assessment of the incidence and severity of PN and its association with genetic polymorphisms. Genomic DNA was isolated from blood samples and 15 Single Nucleotide Polymorphisms (SNPs) were genotyped by Taqman specific assays. The association between PN and SNPs were evaluated by Fisher exact test.ResultsStarting from May 2014 until June 2018 180 pts were enrolled in this study by 20 Italian centers. 170 of these pts could be evaluated for efficacy and toxicity and 159 for polymorphisms analysis. The median age of pts was 60 years old and the biological subtypes were luminal type (64.7%), Her2 positive (18.3%) and triple negative (17%). Pts were pretreated with a median of 5 lines for MBC. The median follow up of this study was 15.4 months with a median number of 4.5 cycles administered (minimum–maximum 1–23). The median overall survival was 12 months. 48.8% of pts experienced a dose reduction, mainly for neutropenia (23.9%) and liver toxicity (12%). 65 pts (38.2%) reported at least one severe toxicity. Neutropenia and neurotoxicity were the most frequent severe AEs (15.3% and 14.7%, respectively); other reported toxicities were osteo-muscular, abdominal or tumor site pain (19.4%), liver toxicity (6.6%), pulmonary toxicity (6.5%) and dermatological toxicity (3.6%). Among the 15 evaluated SNPs, an association with PN was found for rs2233335 and rs7214723.ConclusionsEribulin is a well-tolerated treatment option in MBC. Schedule and dosage modifications were common, but toxicity rarely led to treatment discontinuation. SNPs rs2233335 (G/T and T/T) in the NDRG1 gene and rs7214723 (CC and CT) in the CAMKK1 gene were associated with PN. These findings, if validated, could allow a tailored treatment with eribulin in cancer patients.Trial registration: ClinicalTrials.gov ID: NCT02864030.

Pencil Beam Scanning (PBS) Intensity-Modulated Proton Therapy (IMPT) Chemoradiotherapy for Anal Canal Cancer-Single Institution Experience.

Background: A favourable dose distribution has been described for proton beam therapy (PBT) of anal cancer in dosimetric studies. The relationship between dosimetric parameters in bone marrow and haematologic toxicity, treatment interruptions, and treatment efficacy has also been documented. There are only few references on clinical results of PBT for anal cancer. The primary objective of the retrospective study was to assess the efficacy of pencil beam scanning intensity-modulated proton therapy (PBS IMPT) in the definitive chemoradiotherapy of anal cancer. Secondary objectives were established to identify the risks of acute chronic toxicity risks and to assess colostomy rates. Materials and methods: Patients were treated for biopsy-proven squamous cell cancer (SCC) of the anus at initial or advanced stages. Eligible patients received PBS IMPT at a single institution. Treatment was administered in two volumes: 1-tumour with margins plus involved lymph nodes; 2-regional lymph node groups: perirectal (mesorectal), obturatory, inguinal, internal, external, and common iliac. The total doses of 57.5 GyE and 45 GyE, respectively, were administered in volumes 1 and 2 in 25 fractions, 5 fractions per week, respectively (a simultaneous integrated boost). Concomitant chemotherapy cisplatinum (CDDP) plus 5-FU or CDDP plus capecitabine was administered as per protocol. The treatment effect was assessed using DRE (digital rectal examination) and MRI (magnetic resonance imaging) within the follow-up period. Toxicity was scaled using CTCAE version 4.0 criteria. Results: 39 of 41 patients treated during the period of February 2014-August 2021 were eligible for analysis. All patients completed treatment, 76.9% without interruption. The median treatment time was 35 days (32-35). The median follow-up period was 30 months, 34 patients are alive to-date, 5 patients died prior to the date of analysis, and 2 deaths were unrelated to the primary disease. The 2-year overall survival, relapse-free survival, and colostomy-free survival were 94.2%, 93.8%, and 91.0%, respectively. Complete regression was achieved in 36 patients (92.3%), partial regression was achieved in 2 (5.1%), and immediate progression at end of treatment occurred in 1 patient (2.6%). Salvage resection was indicated for two patients in partial regression and due to severe chronic dermatologic toxicity. The grade 3 and 4 haematological toxicity rates were 7.7% and 5.1%, respectively. The most frequent non-haematological acute toxicities of grade 3-4 observed were dermatitis (23.1%), diarrhoea (7.7%), and dehydration (7.7%). Chronic toxicity emerged predominantly as skin atrophy/ulceration grade 2 (26.5%) and grade 3-4 (5.8%), and radiation proctitis grade 2 (38.2%) and grade 3 (2.9%). Discussion, conclusions: This single-institution study showed the high efficacy of PBS IMPT, achieving a high rate of complete regression. The haematological acute toxicity of grade 3-4 remained low; however, the impact of altered chemotherapy (CDDP instead of mitomycin C) remains unclear. The incidence of other acute toxicities shares similarity with photon therapy investigated in large studies. The acute toxicity completely resolved in all patients, had no lethal outcomes, and never resulted in the necessity for colostomy. By contrast, it was chronic toxicity, skin ulceration, perirectal fistulation, and fibrosis that resulted in salvage surgery and/or the need for a colostomy. A challenging question remains: to what extent can PBT prevent chronic toxicity? Longer follow-up remains necessary.

Immune checkpoint inhibitor-related adverse events in lung cancer: Real-world incidence and management practices of 1905 patients in China.

BackgroundImmune checkpoint inhibitors (ICIs) are the standard treatment for advanced lung cancer, but immune‐related adverse events (irAEs) remain poorly understood, especially in a real‐world setting.MethodsA multicenter observational study was conducted. Medical records of lung cancer patients treated with ICIs at 26 hospitals from January 1, 2015, to February 28, 2021, were retrieved. Types of ICIs included antiprogrammed cell death 1 or antiprogrammed cell death ligand 1 (PD‐L1) monotherapy, anticytotoxic T‐lymphocyte antigen‐4 monotherapy, or combination therapy.ResultsIn total, 1905 patients with advanced lung cancer were evaluated. The median age was 63 (range 28–87) years, and the male/female ratio was 3.1:1 (1442/463). The primary histological subtype was adenocarcinoma (915). A total of 26.9% (512/1905) of the patients developed 671 irAEs, and 5.8% (110/1905) developed 120 grade 3–5 irAEs. Median duration from ICI initiation to irAEs onset was 56 (range 0–1160) days. The most common irAEs were thyroid dysfunction (7.2%, 138/1905), pneumonitis (6.5%, 124/1905), and dermatological toxicities (6.0%, 115/1905). A total of 162 irAEs were treated with steroids and 11 irAEs led to death. Patients with positive PD‐L1 expression (≥1%) and who received first‐line ICI treatment developed more irAEs. Patients who developed irAEs had a better disease control rate (DCR, 71.3% [365/512] vs. 56.0% [780/1145]; p < 0.001).ConclusionsThe incidence rate of irAEs was 26.9% in a real‐world setting. IrAEs might be related to a better DCR, but clinicians should be more aware of irAE recognition and management in clinical practice.

Dermatological toxicity of EGFR inhibitors: pathogenetic rationale and an algorithm for acne-like rash correction

Therapy with epidermal growth factor receptor (EGFR) inhibitors is inevitably accompanied by the phenomena of dermatological toxicity. Being, on the one hand, a favorable prognostic factor for the effectiveness of anticancer therapy, these adverse events are one of the most frequent indications for treatment withdrawal. This article presents the clinical characteristics of a wide spectrum of dermatological adverse events, as well as the pathogenetic rationale for their correction. Algorithms for prescribing of external and systemic therapy based on the assessment of severity of skin lesions and skin appendages involvement are presented.

Novel Hemorrhagic Dermatologic Toxicity Associated with Bruton's Tyrosine Kinase Inhibitor Therapy

Background:Bruton Tyrosine Kinase inhibitors (BTKi), including ibrutinib and acalabrutinib, are an integral part of the treatment paradigm for many B-cell malignancies including chronic lymphocytic leukemia (CLL), mantle cell lymphoma (MCL), and Waldenstrom macroglobulemia (WM). Dermatologic toxicities associated with drugs in this class including petechiae, easy bruising, panniculitis, folliculitis, and aphthous ulcerations have been previously documented (Sibaud et al Am J Clin Dermatol. 2020). The ecchymotic lesions noted in this recent review by Sibaud et al were noted to mimic solar purpura with discrete areas of bruising or hematoma. In the present case series, we present a cohort of patients experiencing an array of skin toxicities during treatment with ibrutinib or acalabrutinib including instances of striking confluent ecchymotic skin lesions.Methods:A retrospective chart review was conducted on patients treated within our health system who had received ibrutinib, acalabrutinib or zanubrutinib treatment. IRB approval was obtained prior to collection of clinical data. Patients who had a dermatologic toxicity including petechiae, ecchymoses, hematoma or vasculitis were identified. Patients were excluded if they were receiving BTKi for graft versus host disease or an indication other than CLL or lymphoma, or if there were insufficient records. Data collection included the BTKi agent and dosing utilized, the age at onset of dermatologic toxicity, the time from initiation of BTKi therapy to the development of dermatologic toxicity, and subsequent treatments following BTKi cessation (if any). Data was compiled and descriptive statistics were obtained.Results:Patients had a median age of 73; five patients were male and two female. Diagnoses included CLL (n = 3), MCL (n = 3), and WM (n = 1). Three were treated with acalabrutinib while 4 received ibrutinib. Two patients received combination therapy with ibrutinib, one with ublituximab and one with ixazomib. The average time to onset of skin toxicity was sooner in those taking acalabrutinib (63 days) versus ibrutinib (642 days). Two of the acalabrutinib-related events were documented within 1 month of therapy initiation. Skin biopsy on one patient treated with acalabrutinib revealed vascular ectasia with non-occlusive thrombotic vasculopathy. Following development of these skin toxicities, therapy with the BTKi was discontinued in only 2 of 7 patients. Three patients were transitioned to an alternative BTKi and two were continued on therapy without modification and without further clinical deterioration.Conclusion:While dermatologic toxicity associated with use of ibrutinib and acalabrutinib has been previously described, this cohort represents, to our knowledge, the first documentation of large confluent BTKi- associated ecchymoses. While several patients in this cohort were transitioned to an alternative BTKi or to a different therapeutic class entirely at the onset of dermatologic toxicity, two continued on the implicated BTKi without alteration in therapy. As demonstrated by these varied approaches, management of BTKi therapy following development of dermatologic toxicity is not standardized, with optimal management determined on an individualized basis through discussion and joint decision making with the patient. [Display omitted] DisclosuresWilliams: Janssen: Consultancy, Research Funding; Pharmacyclics: Research Funding. Flowers: Venthera: Current Employment.

Comparing the PI3K Inhibitors in Hematological Malignancies: Review of Faers

Background:Phosphatidylinositol 3-kinase inhibitors (PI3KI) are a novel class of drugs that are small molecular inhibitors of various isoforms of phosphatidylinositol 3-kinase (PI3K). Over the past decade, various PI3KI have been approved in follicular lymphoma, marginal zone lymphoma, and chronic lymphocytic leukemia. While Copanlisib inhibits P13K-alpha and P13K-delta isoforms, idelalisib inhibits P13K-delta, duvelisib inhibits PI3K-delta and PI3K-gamma, and the recently approved agent umbralisib targets PI3K-delta and casein kinase 1 epsilon with improved selectivity for the PI3K-delta. All the agents except Copanlisib are given orally. Immune-mediated adverse effects like colitis, marrow suppression with infections, and dermatological toxicities are known complications of PI3KI. We did a retrospective analysis of the adverse effects (AE) of the PI3KI in the FDA Adverse Event Reporting System (FAERS).Methods:FAERS public dashboard is a resource through which information related to AEs of treatments reported to the FDA is made available to the public. We investigated the common immune-mediated, infectious, hepatic, and dermatological toxicities of the three PI3KI, idelalisib, copanlisib, and duvelisib for the years 2018 to March 2021. Umbralisib has not much-reported data in FAERS.Results:The data regarding various adverse effects are summarized in Table 1. Idelalisib has the most reported data. Diarrhea is reported to be most common with duvelisib (21.83% of total AE). Though diarrhea is common, colitis is uncommon and least reported with copanlisib (1.15%). Among the patients with colitis, death occurred in 27.2% with idelalisib, 15.3% with duvelisib and 50% with copanlisib. Pneumonitis is most reported with copanlisib (3.45%). Among the patients with pneumonitis, death occurred in 34.7% with idelalisib, none with duvelisib and 50% with copanlisib. Rash is most reported with copanlisib (6.32%) and the incidence of serious dermatological toxicity is uncommon in all the 3 drugs. Rates of neutropenia and thrombocytopenia are overall similar between the drugs except for a slightly higher rate in copanlisib including febrile neutropenia. Infections including pneumonia, urinary tract infection, PJP pneumonia, and CMV reactivation are overall comparable between the 3 drugs. Among the patients with various infections, death occurred in 24.1% with idelalisib, 14.5% with duvelisib and 16.9% with copanlisib. The rate of hepatotoxicity is also comparable between the drugs. Among the patients with hepatic failure, death occurred in 33.3% with idelalisib, 100% with duvelisib and copanlisib.Conclusion:The overall rates of serious adverse effects are comparable between the 3 PI3KI, though diarrhea is most common with duvelisib, pneumonitis, and rash with copanlisib. As these drugs are mainly used in the relapsed refractory setting, many more years of follow-up are needed to get a better idea of real-world data as we have more experience with these drugs. [Display omitted] DisclosuresMaster: Blue Bird Bio: Current holder of individual stocks in a privately-held company.

Characterization and Management of Oral and Dermatological Toxicities in Patients Receiving the CD3 X GPRC5D Bispecific Antibody Talquetamab (JNJ-64407564) for the Treatment of Relapsed and/or Refractory Multiple Myeloma

Background: Talquetamab (JNJ-64407564) is a humanized IgG4 bispecific antibody that targets the CD3 receptor complex on T cells and G-protein-coupled receptor class 5 member D (GPRC5D) a transmembrane receptor protein overexpressed on malignant plasma cells in Multiple Myeloma. After 6.3 months of follow up in RRMM, talquetemab monotherapy at the recommended phase 2 dose yielded an overall response rate of 70%. Talquetemab was well tolerated and here we describe the presentation and management of dermatologic and oral adverse events (AEs) in 78 patients (pts) treated with talquetemab at a single center that is part of a multi-center, multi-national study.Methods: Eligible pts with RRMM were enrolled to the Phase 1, first in human, open-label dose escalation study (NCT03399799) at our site, and received talquetamab intravenously (IV; range 1.5µg/kg -1200µg/kg biweekly or weekly) or subcutaneously (SC; 5µg/kg to 800µg/kg weekly). AEs were graded using CTCAE v4.03.Results: As of July 2021, 78 pts received talquetamab, 53 (67.9%) by IV and 25 (32%) by SC route. Treatment emergent dermatologic AEs were observed in 20 (25.6%) pts. The most common AEs were palmar/plantar desquamation in 22 pts (28.2%, grade 1/2), nail disorders in 14 pts (17.9%, all grade 1), systemic rash in 11 patients (14%, grades 1-3), and injection site reaction in 7 pts (8.9%, all grade 1). Time of onset for dermatologic toxicities was generally within the first 30 days of therapy.In collaboration with dermatology consultation, the management of palmar/plantar desquamation, nail disorders, and injection site reaction has been ammonium lactate 12% cream, triamcinolone 0.1% cream, along with plain Vaseline and Vanicream products applied twice daily.Of the 11 pts with systemic rash, 10 were at or above a dose of 405 µg /kg. Five pts had grade 3 rash requiring dose hold and systemic steroids in conjunction with topical medications. All pts have resumed dosing without recurrence of grade 3 rash. Four of these pts were at a dose level of 800 µg/kg SC. Grade 1-2 rash did not require dose hold and was managed with early intervention of the 3 topical treatments applied to affected areas twice daily.In addition to the above described dermatologic AEs, treatment emergent oral AEs were observed in 38 (48.7%) pts, all grade 1-2. 42 pts developed dysgeusia (53.8%), 16 developed dry mouth (20.5%), and 17 developed dysphagia (21.8% ).Dysgeusia resulted in 3 pts requiring drug interruption. 1 pt requiring dose reduction, and 1 discontinued treatment. The average time to onset for dysgeusia was 26.5 days. Dry mouth resulted in no drug interruptions, reductions, or discontinuations, and had an average onset of 6.7 days. Dysphagia also ranged from grades 1-2, with 3 pts requiring drug interruption. There were no dose reductions or treatment discontinuation. The average time to onset was 41.5 days. Dry mouth, dysgeusia, and dysphagia were more prevalent with higher doses.Along with GI and nutrition consultation, oral AEs have been successfully managed with saliva substitute sprays and rinses. These supportive interventions are instituted promptly at time of onset of symptoms.The above-described treatments for dermatologic and oral AEs were not protocol mandated procedures.DiscussionThe dermatologic and oral AEs associated with talquetamab have unknown etiologies and are currently under investigation. These AEs are typically low grade, rarely require dose holds or modifications, and have been manageable with early and consistent supportive care. Only one patient to date at our center, has discontinued treatment due to an oral or dermatologic side effect. Talquetamab appears to have a have favorable risk/benefit profile in RRMM with durable responses and manageable toxicities. A standardized regimen of topical and oral supportive care appears to be beneficial in the management of dermatological and oral side effects. DisclosuresFarrell: Regeneron: Current Employment. Florendo: Legend Biotech: Current Employment. Catamero: Celgene: Ended employment in the past 24 months, Honoraria; Legend: Honoraria; Oncopeptides: Speakers Bureau. Parekh: Foundation Medicine Inc: Consultancy; Amgen: Research Funding; PFIZER: Research Funding; CELGENE: Research Funding; Karyopharm Inv: Research Funding. Richter: Janssen: Speakers Bureau; Celgene: Speakers Bureau; Adaptive Biotechnologies: Speakers Bureau; Celgene: Consultancy; Janssen: Consultancy; BMS: Consultancy; Karyopharm: Consultancy; Antengene: Consultancy; Sanofi: Consultancy; X4 Pharmaceuticals: Consultancy; Oncopeptides: Consultancy; Adaptive Biotechnologies: Consultancy; Secura Bio: Consultancy; Astra Zeneca: Consultancy. Chari: Janssen Pharmaceuticals: Consultancy, Research Funding; Bristol Myers Squibb: Consultancy, Research Funding; Novartis Pharmaceuticals: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; Pharmacyclics: Research Funding; Seattle Genetics: Consultancy, Research Funding; Takeda Pharmaceutical Company: Consultancy, Research Funding; Karyopharm: Consultancy; Sanofi Genzyme: Consultancy; Oncopeptides: Consultancy; Antegene: Consultancy; Glaxosmithkline: Consultancy; Secura Bio: Consultancy.

Dermatologic adverse events associated with targeted therapies for melanoma

ABSTRACT Introduction The development of new targeted therapies has considerably changed the therapeutic paradigm of melanoma, significantly increasing overall survival (OS) and progression-free survival (PFS). However, skin-related adverse sequelae might occur and impact on patients’ quality of life. Areas covered In this article we will cover the most important dermatological toxicities related to BRAF and MEK-inhibitors, along with updated management strategies. Expert opinion BRAF inhibitors have represented a revolution in the treatment of melanoma. They have improved the outcome of the disease and therefore represent an important option in the management and care of patients with advanced melanoma. Skin toxicity (especially the onset of squamous skin carcinomas) has been considered a major cutaneous side effect and, although the addition of MEK inhibitors in combination has significantly reduced the incidence of skin sequelae, serious skin adverse events might develop anyway and impact significantly on patients’quality of life and on national health system budget. The introduction of BRAF and MEK inhibitors as a new effective adjuvant treatment option for stage III and ulcerated melanoma has proved a significant impact on the risk of recurrence, and may have interesting developments in the near future as a further therapeutic tool.

Pilot Study to Assess the Change in Vaginal Dimensions Following Vaginal Brachytherapy (VBT)

Toxicities related to vaginal brachytherapy can be challenging to capture in patients with endometrial cancer treated with VBT HDR. In this pilot study, we sought to objectively measure the changes in vaginal length and caliber while capturing patient reported acute and chronic toxicities.63 patients with endometrial carcinoma treated with VBT 30 Gy in 3 fractions to the vaginal surface using Ir192 HDR from March 2015 through December 2018 were invited to return for a research visit. 18 patients with AJCC 8th pT1-T2 pNx-N1 cM0 endometrial carcinoma returned to clinic for measurement of vaginal length and diameter using VBT cylinders. Measurements were compared to vaginal length/diameter assessed during the first brachytherapy treatment. Vaginal and vulvar atrophy were assessed. Pain during insertion was measured on a scale of 0 to 10. The patients completed questionnaires regarding vaginal, rectal, urinary and dermatologic toxicities (using CTCAE v5.0). Toxicities were classified as acute if they occurred within the first 2 months after treatment, or chronic if they occurred 2 months after treatment. The mean differences in change between start of VBT and research visit for both vaginal length and diameter were calculated.Median age at time of diagnosis was 69 years (range 46-88). Tumor stage was pT1a 50% (n = 9), pT1b 38.9% (n = 7), and pT2 11.1% (n = 2). Of the 18, 13 (72.2%) had endometrioid tumors, 2 (11.1%) had serous, 2 (11.1%) had mixed, and 1 (5.6%) had clear cell. Median length of time from VBT start until research visit was 43.3 months. The median original vaginal length of the 18 women was 13.9 cm (range 11 - 18 cm). The median original cylinder size was 3.0 cm (range 2.5-3.0 cm). The mean decrease in vaginal length from VBT start to visit date was 1.4 cm, which was significantly different from zero (P = 0.0002). The mean decrease for the vaginal diameter was 0.03 cm which was not significantly different from zero (P = 0.6). On exam, 12 (66.6%) had grade 1-2 vaginal atrophy and 5 (27.8%) had grade 1 vulvar atrophy. Pain during cylinder placement was median of 1 (range 0-10); 77.8% had 0-2 out of 10 pain. Patient-reported acute grade 1-2 toxicities included dermatitis (n = 1), and cystitis (n = 1). There were no patient-reported grade 3-5 acute or chronic toxicities. Patient-reported chronic grade 1-2 toxicities included cystitis (n = 2), vaginal stenosis (n = 2), and diarrhea (n = 1).In our pilot study of 18 patients treated with VBT with 30 Gy in 3 fractions to the vaginal surface, we found a statistically significant average vaginal shortening after approximately 4.5 years of average follow-up. We observed no significant change in vaginal diameter. VBT was followed by infrequent patient-reported grade 1-2 acute or chronic toxicities. This report adds to the scarce literature of objective data on vaginal sequelae of VBT for endometrial carcinoma.K. Nieto: None. B. Levine: None. D.R. Brown: None. H.S. McGinnis: None. C.M. Lanier: None. K. Hines: None. K.M. Greven: None.

Severe Toxicity and Provider-Reported Subjective Symptoms in Patients With Vulvar Cancer Receiving Curative-Intent Radiotherapy

Definitive or adjuvant radiotherapy (RT) for vulvar squamous cell carcinoma (VSCC) is associated with significant toxicity that can negatively impact a patient's health-related quality of life (HRQoL). Given the rarity of this disease, data on the incidence of acute and late severe toxicity as well as the real-world late-symptom burden from a modern cohort are lacking.Patients with VSCC treated with adjuvant or definitive radiotherapy with curative intent from 2009-2020 within our multi-center academic medical system were retrospectively analyzed. Treatment-related acute and late (≥3 months after RT) grade 3 or greater toxicities assessed by CTCAE version 5.0 were recorded. All provider-reported subjective symptoms (PRSS) documented from the date of RT completion to the date of last follow up were recorded. Kaplan-Meier model was used to estimate one-year overall survival (OS) and progression-free survival (PFS).Thirty-nine patients received either definitive (n = 22, 56.4%) or adjuvant (n = 17, 43.6%) RT to a median dose of 64.4 Gy and 59.4 Gy, respectively. Five patients (3 definitive, 2 adjuvant) received a brachytherapy boost with a median total EQD2 of 84.3 Gy. Intensity-modulated or volumetric-modulated arc RT was used in 34 (87.2%) of patients, and 22 patients (56.4%) received concurrent chemotherapy. Median follow up time was 12.5 months (Q1-Q3: 2.8-31.3 months) for all patients and 14.9 months (3.8-33.2) for alive patients. Seventy-four percent of patients (FIGO Stage I; n = 10, II; n = 5, III; n = 10, IVA; n = 4) had a complete response based on clinical (n = 26) or pathologic (n = 3) criteria, including 16 treated with adjuvant RT and 13 treated with definitive RT. The 1-year estimated OS and PFS were 90.4% and 90.5%, respectively. The incidence of acute grade ≥3 toxicity was 35.9% (n = 14). Acute grade ≥3 skin toxicity was most common (n = 10, 25.6%), followed by urinary (n = 1, 2.6%), gastrointestinal (n = 1, 2.6%), hematologic (n = 1, 2.6%), and fatigue (n = 1, 2.6%). Five (12.8%) patients experienced late grade ≥3 toxicity, including 2 patients (5.1%) with grade 3 dermatologic toxicity, 2 patients (5.1%) with grade 4 skin toxicity, and 1 patient (2.6%) with grade 3 gastrointestinal toxicity. Among the 32 patients with PRSS data available, 6 (15.3%) reported dyspareunia or inability to have sexual intercourse, 5 (12.8%) noted skin discoloration or fibrosis, 11 (28.2%) reported long-term vaginal pain or irritation, and 8 (20.5%) required long-term opiate pain medication.RT for VSCC is associated with considerable rates of severe acute and late toxicity as well as PRSS that affect both a patient's physical functioning and HRQoL. Taken together with the high rates of disease control and survival, these data argue for improved patient-reported outcome measures and investigation of therapeutic de-escalation strategies.N.S. McCall: Honoraria; PrecisCA.T.Y. Eng: Stock; Amgen. J.W. Shelton: None. S. Hanasoge: None. P.R. Patel: None. A.B. Patel: Honoraria; American College of Radiology. A. McCook: None. J. Switchenko: None. T. Cole: None. N. Khanna: None. C. Han: None. A.N. Gordon: None. K. Starbuck: None. J.S. Remick: None.

Diverse landscape of dermatologic toxicities from small-molecule inhibitor cancer therapy.

Advances in molecular biology and genetics have contributed to breakthrough treatments directed at specific pathways associated with the development of cancer. Small-molecule inhibitors (Nibs) aimed at a variety of cellular pathways have been efficacious; however, they are associated with significant dermatologic toxicities. We conducted a comprehensive review of dermatologic toxicities associated with Nibs categorized into the following five groups: (a) mitogen-activated protein kinase; (b) growth factor/multi-tyrosine kinase; (c) cell division/DNA repair; (d) signaling associated with myeloproliferative neoplasms; and (e) other signaling pathways. Prospective phase I, II, or III clinical trials, retrospective literature reviews, systematic reviews/meta-analyses, and case reviews/reports were included for analysis. Dermatologic toxicities reviewed were associated with every class of Nibs and ranged from mild to severe or life-threatening adverse skin reactions. Inflammatory reactions manifesting as maculopapular, papulopustular/acneiform, and eczematous lesions were frequent types of dermatologic toxicities seen with Nibs. Squamous cell carcinoma with keratoacanthoma-like features was associated with a subset of Nibs. Substantial overlap in dermatologic toxicities was found between Nibs. Dermatologic toxicities from Nibs are diverse and may overlap between classes of Nibs. Recognition of the various types of toxicities from Nibs is critical for patient care in the era of "oncodermatology/dermatopathology."

Cutaneous toxicities from targeted therapies used in oncology: Literature review of clinical presentation and management.

With the development of molecular targeted therapies, a wide array of dermatologic toxicities is appearing. Their prevention, recognition, and management by dermatologists is critical to ensure antineoplastic treatment continuation. The objective of this study was to provide a literature review of the most common dermatologic toxicities due to targeted therapies in oncologic patients, including their clinical presentation, prevention, and management.

Dermatologic toxicities of targeted antineoplastic agents and immune checkpoint inhibitor therapy in pediatric patients: A systematic review.

Cutaneous adverse events (cAEs) from targeted antineoplastic agents and immune checkpoint inhibitors are common in children with cancer and may lead to dose reduction or cessation of critical oncologic treatment. Timely diagnosis and proper management of cAEs in pediatric oncology patients is essential to optimize ongoing cancer-directed therapy and improve quality of life. This systematic review of published studies summarizes dermatologic toxicities to targeted anticancer treatments and immune checkpoint inhibitors.

Safety of Immune Checkpoint Inhibitors in Elderly Patients: An Observational Study.

Background: Immunotherapy has completely changed the treatment of solid tumors. Although immune checkpoint inhibitors (ICIs) seem to be an appealing alternative to chemotherapy, especially in elderly patients, due to a more tolerable toxicity profile, they can lead to a peculiar variety of immune-related adverse events (irAEs). However, data on tolerability and outcome of ICIs in the elderly are lacking due to poor accrual in clinical trials of these patients. Methods: We performed a retro-prospective analysis on patients treated with single agent anti-PD-L1/PD-1 at the Clinical Oncology Unit, Careggi University Hospital, from March 2016 to March 2020. Data on the treatment responses, type and severity of irAEs, as well as the corticosteroids (CCS) dosage used for irAEs and the discontinuation rate, were described per each patient, according to two different age-based cohorts of patients (< or ≥70 years). Results: We reported a lower incidence of all-grade toxicity in elderly compared to younger patients (64.9% vs. 44.9%, p = 0.018). The two age-cohorts showed a different profile of irAEs. Endocrine irAEs were significantly higher in younger patients (39.7% vs. 21.7%, p = 0.002), while dermatologic toxicities were more common in the older group (35.0% vs. 11.3%, p = 0.047). Use of CCS and treatment discontinuation rate do not differ significantly between the two age groups. Conclusion: Our findings suggest that treatment with ICIs in elderly populations is safe and feasible. Patients over 70 years are more prone to develop skin irAEs, while younger patients are more subject to experience endocrine toxicities.

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

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

Treatment recommendations for nail unit toxicities secondary to targeted cancer therapy based on collective experience and evidence-based literature review

To the Editor: Dermatologic toxicities are often the earliest-presenting and highest-incidence adverse events (AEs) due to targeted anticancer therapies and immunotherapies.1 Nail unit toxicities due to immunotherapy are caused by nonspecific immune activation. Targeted therapies, particularly mitogen-activated protein kinase pathway inhibitors, lead to epidermal thinning of the nailfolds and periungual tissue, increasing susceptibility to trauma and penetration by nail plate fragments. Paronychia may develop and evolve into onychocryptosis.

Female sex is associated with higher rates of dermatologic adverse events among patients with melanoma receiving immune checkpoint inhibitor therapy: A retrospective cohort study

To the Editor: The significance of sex as a risk factor for the development of dermatologic toxicities caused by immunotherapy remains unclear. In a study on non–small cell lung cancer patients receiving immune checkpoint inhibitors (ICIs), women were observed to have higher rates of nondermatologic immune-related adverse events (irAEs) (such as endocrinopathies and arthralgias), with premenopausal women appearing to be at a greatest risk.1 We evaluated the impact of sex on the development of dermatologic toxicities in melanoma patients receiving ICIs.