Dermatologic Toxicity Research Articles

First Cycle Toxicity and Survival in Patients with Rare Cancers Treated with Checkpoint Inhibitors.

Associations between immune-related adverse events (irAEs) from checkpoint inhibitor therapy and outcomes have been previously evaluated, with most prior research finding a positive association between toxicity and survival. This prior research has generally reported on more common tumor types. We use a unique data resource of a federally-funded basket trial ((NCT02834013) for patients with rare cancers (N = 684) to evaluate associations between irAEs and overall survival and progression-free survival. Patients were treated with nivolumab and ipilimumab; the trial was opened at > 1000 sites. Landmark Cox regression models were used to assess first cycle irAE associations with progression-free and overall survival. We found that grade 1-2 treatment-related irAEs in the first cycle of therapy were associated with longer overall survival (OS) (multivariable hazard ratio, 95% confidence interval, p-value: 0.61, 0.49-0.75, p < .001) compared to no treatment-related irAE, while grade 3-4 irAEs were associated with shorter OS (HR = 1.41, 95% CI = 1.04-1.90, p = .025). Similar, but weaker, associations were observed with progression-free survival (PFS) and grade 1-2 treatment-related irAEs: HR = 0.83, 95% CI = 0.67-1.01, p = .067 and grade 3-4: HR = 1.35, 95% CI = 1.02-1.78, p = .037 compared to no treatment-related irAEs. Grade 1-2 dermatologic toxicity was associated with improved OS compared to other grade 1-2 toxicities (HR = 0.67, 95% CI = 0.52-0.85, p = .002). There was no significant OS difference between patients with Grade 1-2 fatigue, gastrointestinal, metabolic, hepatic, endocrine, and thyroid toxicities vs other Grade 1-2 toxicities. In this large cohort of patients with rare tumors receiving checkpoint inhibitor therapy, grade of irAE in the first cycle was predictive for survival.

Lichenoid dermatitis induced by abemaciclib in a patient with HR+/HER2- breast cancer

Cyclin-dependent kinase (CDK) 4/6 inhibitors, such as palbociclib, ribociclib, and abemaciclib, are widely used in combination with endocrine therapy for the treatment of hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) breast cancer. Despite their efficacy, these drugs are associated with a range of adverse events, including dermatologic toxicities. This case report presents a rare instance of lichenoid dermatitis in a 48-year-old woman following treatment with abemaciclib. The patient developed erythematous, edematous plaques and papules on her hands and forearms, which resolved after discontinuation of the drug and treatment with topical corticosteroids. This report highlights the need for awareness of cutaneous side effects associated with CDK4/6 inhibitors, particularly abemaciclib.

New emerging treatment options for metastatic melanoma: a systematic review and meta-analysis of skin cancer therapies.

Skin cancer, notably melanoma, poses a significant global health burden, with rising incidence and mortality rates. While therapeutic advancements have improved outcomes, metastatic melanoma remains challenging to treat. This study aims to systematically review systemic treatment options for advanced melanoma, focusing on efficacy and safety in the first-line setting. Through a comprehensive search and meta-analysis of randomized controlled trials conducted from 2013 to 2023, 11 studies encompassing 2816 participants were analyzed. Treatment options included BRAF inhibitors (vemurafenib, dabrafenib), MEK inhibitors (trametinib, cobimetinib), and immune checkpoint inhibitors (ipilimumab). Combined therapy with vemurafenib, cobimetinib, and ipilimumab demonstrated superior overall survival (OS) and progression-free survival (PFS) compared to monotherapy, with a significant odds ratio (OR) of 6.95 (95% CI: 4.25-9.64, p < 0.00001) for OS and 2.49 (95% CI: 1.42-3.56, p < 0.00001) for PFS. Additionally, dabrafenib and trametinib combination therapy showed improved outcomes with favorable tolerability, including a significant reduction in adverse event (AE) risk, with an OR of 2.20 (95% CI: 1.72-2.81). Furthermore, our analysis highlighted vemurafenib-associated dermatological toxicities, emphasizing the need for effective management strategies. The study underscores the evolving treatment landscape in melanoma management, with a potential shift towards immune checkpoint inhibitors in the adjuvant setting, particularly for BRAF-mutated disease. However, limitations in meta-analysis methodologies and the need for long-term investigations into treatment implications on survival and quality of life underscore the importance of continued research.

Post-marketing drug safety surveillance of enfortumab vedotin: an observational pharmacovigilance study based on a real-world database.

Enfortumab vedotin (EV) is an antibody-drug conjugate (ADC) that has been approved by the FDA for patients with locally advanced or metastatic urothelial carcinoma (UC). This study presents a comprehensive pharmacovigilance analysis of the post-marketing safety profile of EV in the real-world based on the US Food and Drug Administration Adverse Event Reporting System (FAERS). Adverse event (AE) reports regarding EV between January 2020 and December 2023 were obtained from the FAERS database. The standardized MedDRA query (SMQ) narrow search AEs on the preferred term (PT) level were used. Disproportionality analysis was performed to identify the AE signals for EV with the reporting odds ratio (ROR), proportional reporting ratio (PRR), multi-item gamma Poisson shrinker (MGPS), and Bayesian confidence propagation neural network (BCPNN). A total of 2,216 reports regarding EV were included in the present study. SMQ analysis results indicated that a stronger strength signal was found in severe cutaneous adverse reactions, retroperitoneal fibrosis, and peripheral neuropathy. A total of 116 significant disproportionality PTs referring to 14 system organ classes (SOCs) were retained by disproportionality analysis, with 49 PTs not listed on the EV drug label. Frequently reported EV-related AEs included rash, peripheral neuropathy, decreased appetite, alopecia, and pruritus. The time to onset of the majority of EV-related AEs was within 30 days (66.05%), with only 0.73% events occurring after 1 year. The disproportionality analysis highlights that dermatologic toxicity and peripheral neuropathy were the major AEs induced by EV. The potential AEs not listed on the drug label were mainly related to gastrointestinal, hepatic, and pulmonary events. Further research is needed to confirm and explore the EV-related AEs in clinical practice.

Multiple Endocrine Toxicities in a Metastatic Cutaneous Melanoma Patient Treated with Checkpoint Inhibitors

Metastatic cutaneous melanomas are typically treated with first-line checkpoint inhibitors, such as the anti-PD-1 antibody nivolumab and the anti-CTLA-4 antibody ipilimumab. Common immune-related adverse events (irAEs) from these therapies include dermatological, gastrointestinal, and endocrine toxicities. We present a case involving a 51-year-old woman with a prior medical history of Basedow's disease and multinodular goiter, who was diagnosed with metastatic cutaneous melanoma in 2019. Post-surgical intervention addressed most metastatic sites, leaving behind an inoperable axillary adenopathy. Initial treatment consisted of nivolumab (1 mg/kg) combined with ipilimumab (3 mg/kg). During this dual checkpoint inhibitor therapy, the patient developed hepatitis and primary hypothyroidism, prompting the discontinuation of ipilimumab. Monotherapy with nivolumab was subsequently administered. While on nivolumab, the patient developed additional irAEs, including type 1 diabetes mellitus and primary adrenal insufficiency. Despite these significant endocrinopathies, continuation of immunotherapy was permitted, ultimately resulting in a complete response.

Management of Skin Toxicities in Cancer Treatment: An Australian/New Zealand Perspective.

Cancer systemic therapeutics and radiotherapy are often associated with dermatological toxicities that may reduce patients' quality of life and impact their course of cancer treatment. These toxicities cover a wide range of conditions that can be complex to manage with increasing severity. This review provides details on twelve common dermatological toxicities encountered during cancer treatment and offers measures for their prevention and management, particularly in the Australian/New Zealand context where skincare requirements may differ to other regions due to higher cumulative sun damage caused by high ambient ultraviolet (UV) light exposure. Given the frequency of these dermatological toxicities, a proactive phase is envisaged where patients can actively try to prevent skin toxicities.

DIPG-93. OVERALL EXPERIENCE OF TWO PHASE I CLINICAL TRIALS WITH FOCUSED ULTRASOUND-MEDIATED BLOOD BRAIN BARRIER OPENING IN CHILDREN, ADOLESCENTS, AND YOUNG ADULTS WITH PROGRESSIVE DIPG/DMG USING A NEURONAVIGATION-BASED DEVICE

Abstract OBJECTIVES DIPG/DMG is a fatal brain tumor developing in delicate areas of the brain with a median overall survival of 1 year. The dismal outcome is partly due to the blood-brain barrier (BBB) which poses a major challenge to delivering effective therapeutic agents. Over the past 4 years we opened two Phase I clinical trials using Delsona focused ultrasound (FUS) device developed at Columbia University to treat pediatric and AYA patients with relapsed DMG. In the first study, we delivered FUS with concomitant panobinostat and during the second study we gave oral etoposide. Here we present our experience of delivering neuronavigation based FUS for pediatric patients with progressive DMG. METHODS Pediatric and AYA patients with biopsy proven DIPG/DMG at disease progression were enrolled (FUS with oral panobinostat: NCT04804709 and FUS with oral etoposide: NCT05762419). Patients were allowed to have prior therapies, including radiation and reirradiation. FUS was delivered over the course of six or four cycles respectively. MRI was performed to validate BBB-opening and closure. RESULTS During the FUS-panobinostat study, we treated 3 patients. The study was closed prematurely when panobinostat was taken off the US market. In the FUS-etoposide study, we have already treated 2 patients (the study is currently open). For the two trials combined, we delivered over twenty-five FUS treatments. Four of the five patients treated had achieved BBB-opening. Two patients in the FUS and panobinostat study showed improvement in their neurological symptoms. The average time for FUS-delivery was approximately 47 minutes. All treatments were performed in the outpatient settings in the Department of Radiation Oncology. Side effects from FUS was limited to one grade 1 dermatological toxicity. CONCLUSION FUS-mediated BBB-opening delivered as an outpatient procedure is feasible, to date, in children with relapsed DIPG/DMG. Further studies are needed to assess for efficacy.

LGG-55. DIFFERENTIAL TOXICITY PROFILE OF INDIVIDUAL MEK INHIBITORS: A MULTI-INSTITUTION RETROSPECTIVE REVIEW

Abstract BACKGROUND Most pediatric low-grade gliomas (pLGGs) are driven by molecular aberrations in the mitogen-activated protein kinase pathway (MAPK), which can be targeted by novel agents such as MEK inhibitors (MEKi.) However, MEKi use is accompanied by a varied side effect profile, with the most severe dose-limiting effects involving dermatologic, cardiac, and ophthalmic toxicities. METHODS Multi-institutional retrospective chart review of patients less than 25 years of age who underwent MEKi monotherapy between 2015-2022 was conducted. Data was collected from 4 sites, including Connecticut Children’s, St. Louis Children’s Hospital, Cardinal Glennon Children’s Hospital, and Children’s Hospital of Philadelphia. RESULTS Ninety-six patients were included in the analysis; 54 (56.4%) with brain tumors and 56 (58.3%) with germline mutation in NF-1. Forty-nine (51%) received trametinib, 42 (43.8%) selumetinib, 5 (5%) binimetinib. Of 42 patients with skin toxicity data available, 35 (83%) had cutaneous toxicity, with the most prevalent being acneiform rash (40.0%), followed by maculopapular rash (28.6%) and eczematous dermatitis (11.4%). The mean number of cutaneous skin toxicities was 2.4 (trametinib group = 2.2, selumetinib group = 2.6). Eighteen of 96 (18.8%) patients experienced cardiac toxicity, of which 11 (61.1%), experienced reduction in left ventricular ejection fraction (6 trametinib, 5 selumetinib), 4 (22.2%) developed pericardial effusions. 10 of 96 (10.4%) patients experienced ophthalmic toxicities, most commonly blurred vision (30.0%). Other toxicities included elevated CK (36, 37.5%), anemia (32, 33.3%), and eosinophilia (17, 17.7%). CONCLUSION There was not an observable clinically relevant difference in toxicities between MEKi, with skin toxicity the most prevalent. The prevalence of cardiac toxicity in the patient cohort reinforces the need for appropriate monitoring via echocardiography. MEKi remain an excellent option for therapy for LGG but with the need for continued supportive care and monitoring.

Correlations between first cycle toxicity and overall survival in patients with rare cancers treated with immune checkpoint inhibitors (NCI/SWOG S1609).

2655 Background: Associations between immune-related adverse events (irAEs) from checkpoint inhibitor therapy and outcomes have been previously evaluated, with most prior research finding a positive association between toxicity incidence and overall survival. This prior research has generally reported on more common tumor types. We use a unique data resource of a federally funded basket trial (NCT02834013) for patients with rare cancers to evaluate associations between irAEs and overall survival (OS) and progression-free survival (PFS) in a cohort of patients treated with combination checkpoint inhibitor therapy. Methods: We evaluated irAEs observed in the first cycle (6 weeks) of therapy that were possibly, probably, or definitely related to treatment; irAE grade was based on CTCAEv5. Patients received ipilimumab [1mg/kg intravenously (IV) every 6 weeks] plus nivolumab (240mg IV every 2 weeks). Landmarks methods were used to avoid immortal-time bias; PFS and OS were analyzed from day 43 with patients who died or progressed before that date excluded from analyses. Cox regression analyses were used to evaluate covariate associations. Results: We found that grade 1-2 treatment-related irAEs in the first cycle of therapy were associated with longer OS (multivariable hazard ratio, 95% confidence interval, p-value: 0.61, 0.49-0.75, p&lt;0.001) compared to no treatment-related irAE in the first cycle, while grade 3-4 irAEs were associated with shorter OS (HR=1.41, 95% CI=1.04-1.90, p=0.025). Similar, but weaker, associations were observed with PFS, grade 1-2 treatment-related irAEs: HR=0.83, 95% CI=0.67-1.01, p=0.067 and grade 3-4: HR=1.35, 95% CI=1.02-1.78, p=0.037 compared to no treatment-related irAE in the first cycle. Grade 1-2 dermatologic toxicity were associated with improved OS compared to other grade 1-2 toxicities (HR=0.67, 95% CI=0.52-0.85, p=0.002). There were no significant differences between OS among patients with Grade 1-2 gastrointestinal, metabolic, hepatic, endocrine, and thyroid toxicities and fatigue and other Grade 1-2 toxicities. Conclusions: In this large cohort of patients with rare tumors receiving ipilimumab and nivolumab grade of irAE in the first cycle of therapy was prognostic for survival.

Real life data of KEYNOTE 522: The Cleveland Clinic experience.

e12612 Background: Triple-negative breast cancer (TNBC) constitutes approximately 15% of all breast cancers and predominantly affects younger women with a disproportionate impact on Black and Hispanic ethnicities. Historically, neoadjuvant therapy centered around chemotherapy alone. However, the KEYNOTE 522 trial has demonstrated improved outcomes with the incorporation of the PD-1 inhibitor Pembrolizumab alongside neoadjuvant chemotherapy. Methods: A retrospective cohort analysis of 106 patients treated with the KEYNOTE 522 regimen within Cleveland Clinic from January 2020 to July 2023. The objective is to evaluate the real-life experience, particularly concerning treatment tolerance and pathologic complete response rates (PCR). Results: Among the 106 female patients, 6.6% completed full neoadjuvant therapy without reporting adverse events (AE), achieving a 71.42% PCR rate. Complications were reported in various subgroups: 54.72% associated with paclitaxel and carboplatin, with discontinuation rates of 60.34%, reduction rates of 33.02%, and full continuation rates of 6.9%. The most prevalent AE included cytopenia (46.55%) and febrile neutropenia, along with other infections (27.59%). For patients discontinuing paclitaxel and carboplatin, the PCR was 68.57%, while with dose reductions, it was 68.75%. Complications related to doxorubicin and cyclophosphamide were reported in 16.04% of patients, with 47.06% either discontinuing or reducing dose, and 5.88% continuing full therapy. Febrile neutropenia, along with other infections (64.71%) and cytopenia (23.53%) were the prominent AE. The PCR for patients discontinuing or reduced doxorubicin and cyclophosphamide was 62.50%. Pembrolizumab-related complications were reported in 16.98% of patients, with a 50% discontinuation rate. The most common AE was dermatologic toxicities (27.78%). The PCR for patients discontinuing pembrolizumab was 83.33% versus 62.5% for those continuing full therapy. Conclusions: This retrospective analysis highlights infections and cytopenias as the primary adverse reactions. Notably, the dose reduction or discontinuation of agents did result in a deterioration of PCR rate compared to patients completing full therapy. Remarkably, PCR was improved for the pembrolizumab discontinuation group, perhaps suggesting a correlation between autoimmune toxicities and improved response. Additional prospective study with larger sample size is needed to understand whether all patients benefit from completing the Keynote 522 regimen. [Table: see text]

Associations of early adverse events with clinical outcomes in patients with NSCLC treated with EGFR tyrosine kinase inhibitors.

e20551 Background: Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR TKIs) constitute the primary treatment modality for EGFR-mutant non-small cell lung cancer (NSCLC). While efficacious, EGFR TKIs are associated with adverse events (AEs) like dermatologic toxicities, diarrhea, and stomatitis. This study examined the prognostic implications of these on-target AEs in NSCLC patients receiving EGFR TKI therapy. Methods: A retrospective cohort study was conducted, encompassing advanced NSCLC patients treated with first-line EGFR TKIs within two distinct healthcare delivery systems in Taiwan between June 2011 and December 2019. Patients were stratified by TKI type, and those who had received AE reliever medications within 180 days prior to EGFR TKI initiation were excluded. We examined correlations between AEs and key endpoints: time to next treatment (TTNT) and overall survival (OS). To minimize immortal time bias, a landmark analysis at 60 days post-treatment initiation was utilized. On-target AEs were identified based on the issuance of at least two prescriptions for AE management on different dates within this period. Multivariable Cox proportional hazards models were utilized to evaluate the association between AEs and clinical endpoints, and a random-effects meta-analysis was performed to combine findings from both institutions. Results: Our analysis included 1,605 patients on gefitinib, 848 on erlotinib, and 1,236 on afatinib. Despite potential variations in AE reporting due to prescribing behaviors, the incidence of AE within the first 60 days of treatment was highest for afatinib, particularly with diarrhea (76.7%) and stomatitis (14.9%), followed by erlotinib with notable skin reactions (49.4%). Gefitinib showed the lowest incidence rates across all examined AEs. Of note, afatinib-treated patients who experienced diarrhea within the initial 60 days demonstrated a statistically significant extension in OS (HR 0.75, 95% CI 0.60-0.92). No significant prognostic link was found for other AEs in afatinib users or any AEs among users of gefitinib and erlotinib. Sensitivity analyses, incorporating modified AE definitions, corroborated these outcomes. Conclusions: Identifying AEs via prescription records for symptom relief poses methodological challenges and introduces uncertainty. Nevertheless, the occurrence of diarrhea within the first 60 days of therapy emerged as a significant predictor of enhanced OS in EGFR-mutant NSCLC patients receiving afatinib. This finding suggests a potential prognostic implication. The correlation was not evident in patients treated with first-line gefitinib or erlotinib.

Current status of PD-(L)1 inhibitor usage in advanced or metastatic non-small cell lung cancer: A national survey of oncologists in China.

e20559 Background: The aim of the present study conducted by Chinese Society of Clinical Oncology Expert Committee on Immunotherapy was to obtain real-world information on the use of PD-(L)1 inhibitors for non-small cell lung cancer (NSCLC) in different regions of China via a national questionnaire survey for oncologists. Methods: This survey was distributed online to cancer-related medical departments in 202 first-tier to fourth-tier cities of China between March to April 2023. The national survey consisted of four sections regarding oncologists’ concerns about immunotherapy as follows: treatment choice, response assessment, treatment duration, and management of immune-related adverse events (irAEs). Results: A total of 2,018 oncologists completed this survey. For advanced squamous (SQ) and non-squamous (NSQ) NSCLC without targetable genetic alterations, PD-(L)1 inhibitor-based regimens were the most widely used first-line treatment regimen (SQ: 52%, NSQ: 46%), followed by chemotherapy alone (SQ: 37%, NSQ: 37%) and other regimens (SQ: 11%, NSQ: 17%). The average treatment duration of 1L PD-(L)1 inhibitor-based regimens in SQ NSCLC and NSQ NSCLC were 6.4 and 6.2 cycles, respectively. 67% of oncologists may discontinue immunotherapy or change regimens when the first radiographic tumor assessment was SD per RECIST 1.1. Other reasons for early discontinuation of PD-(L)1 inhibitors before PD or unacceptable toxicity included economic reasons (78%) and patients’ low willingness to continue immunotherapy even they reached CR/PR (62%). Oncologists in the second-tier cities and below were more likely to discontinue immunotherapy when the tumors were stable, with shorter treatment duration of 5.7 cycles versus 7.1 cycles in the first-tier cities. The most common irAEs included dermatologic, endocrine, pulmonary, gastrointestinal, and hepatic toxicities. Conclusions: PD-(L)1 inhibitor-based regimens have become the priority choice for advanced NSCLC in China, however, the status of standardized continuous use of immunotherapy is obviously insufficient. There is a gap between clinical practice and clinical trials regarding PD-(L)1 inhibitor usage, which need more attention. [Table: see text]

Distinct Characteristics and Changes in Liver Function of Patients with Hepatocellular Carcinoma Treated with Atezolizumab Plus Bevacizumab for More Than 1 Year.

Since 2020, atezolizumab plus bevacizumab (Ate/Bev) has been the standard first-line therapy for unresectable hepatocellular carcinoma (HCC), but long-term treatment studies are limited. This study evaluated the clinical characteristics and effects of Ate/Bev for over 1 year. This study included patients with unresectable HCC treated with first-line Ate/Bev between May 2020 and April 2022. Those receiving Ate/Bev for 1 year or more were classified as the long-term treatment group. Of 246 patients, 69 (28.0%) were in the long-term treatment group, which comprised more proportions of intrahepatic tumor burden < 25%, Eastern Cooperative Oncology Group 0, and a lower proportion of portal vein tumor thrombosis than the short-term treatment group. The long-term treatment group had a higher incidence of atezolizumab-related thyroid dysfunction (31.9% vs. 10.7%, p < 0.001; median time to onset [mTTO], 2.8 months), dermatologic toxicity (29.0% vs. 14.7%, p=0.017; mTTO, 3.3 months), bevacizumab-related hypertension (44.9% vs. 22.0%, p=0.001; mTTO, 4.2 months), and proteinuria (69.6% vs. 38.4%, p < 0.001; mTTO, 6.8 months), compared to the short-term treatment group. Regarding liver function in the long-term treatment group, patients initially classified as Child-Pugh class A decreased from 87.0% to 75.4%, and albumin-bilirubin grade 1 decreased from 68.1% to 50.7% after 1 year of treatment. The Ate/Bev long-term treatment group had a lower intrahepatic tumor burden, less portal vein tumor thrombosis, and better performance status and liver function at baseline. Atezolizumab-related immunological adverse events emerged relatively early in treatment compared to the bevacizumab-related. Additionally, some patients demonstrated liver function deterioration during long-term Ate/Bev treatment.

A rare incidence of severe dermatological toxicities triggered by concomitant administration of all-trans retinoic acid and triazole antifungal in patients with acute promyelocytic leukemia: a case series and review of the literature

BackgroundAll-trans retinoic acid (ATRA) is an indispensable part of the treatment of acute promyelocytic leukemia (APL). Although, mild cutaneous toxicities like mucocutaneous xerosis, rash, and pruritus are well reported, ATRA associated severe dermatological toxicities are extremely rare. ATRA is primary metabolized by cytochrome P450 (CYP450) enzyme system, and triazole antifungals are notorious for their strong inhibitory effect on CYP450.Case presentationThree Asian APL patients experienced rare ATRA-induced severe dermatological toxicities: exfoliative dermatitis (ED) in cases 1 and 2, and necrotic scrotal ulceration in case 3. Both case 1 (33-year-old female), and case 2 (28-year-old male) landed in emergency department with dehydration, generalized skin erythema and xerosis during their induction chemotherapy. Both of these patients also developed invasive aspergillosis and required concomitant triazole antifungals during their chemotherapy. For ED, intravenous fluids and broad-spectrum antibiotics were started along with application of local emollients to prevent transdermal water loss. Although their general condition improved but skin exfoliation continued with complete desquamation of palms and soles. Dermatology was consulted, and clinical diagnosis of ED was established. Discontinuation of ATRA resulted in complete resolution of ED. Case 3 (15-year-old boy) reported two blackish mildly tender scrotal lesions during induction chemotherapy. He also had mucocutaneous candidiasis at presentation and was kept on triazole antifungal. Local bacterial & fungal cultures, and serological testing for herpes simplex virus were reported negative. Despite adequate local care and optimal antibiotic support, his lesions persisted, and improved only after temporary discontinuation of ATRA. After a thorough literature review and considering the temporal association of cutaneous toxicities with triazole antifungals, we speculate that the concomitant use of triazole antifungals inhibited the hepatic metabolism of ATRA, resulting in higher serum ATRA concentration, and markedly accentuated cutaneous toxicities in our patients.ConclusionBy highlighting this crucial pharmacokinetic interaction, we want to caution the fellow oncologists to be mindful of the inhibitory effect of triazole antifungals on CYP450. We propose using a non-myelosuppressive combination of ATRA and arsenic trioxide for management of APL hence, obliterating the need of prophylactic antifungals. However, in the event of invasive fungal infection (IFI), we suggest using alternative class of antifungals.

Syndrome de Stevens-Johnson induit par la capécitabine : à propos d’un cas avec revue de littérature

IntroductionCapecitabine is an oral fluoropyrimidine carbamate, analog of 5-fluorouracil. It is widely used for many malignant tumors. Hand-foot syndrome is the most common dermatological toxicity associated with capecitabine and Stevens-Johnson syndrome is the rarest manifestation. We report a case of Stevens-Johnson syndrome induced by capicitabine. Case presentationA 49-year-old patient, hospitalized in oncology for the management of a mucinous colorectal adenocarcinoma with peritoneal metastases. He was treated with capecitabine 3500mg per day. The patient presented diffuse pigmented lesions and an erosive scrotal lesion with dysphagia to solids and liquids, vomiting and non-bloody diarrhea, which occurred 5 days after the onset of the treatment. The clinical examination found an altered patient. The skin examination found a pigmented desquamative plaque on the face, diffuse atypical target lesions, a pigmented plaque on the palms of both hands, a scrotal erosion and cheilitis. The histology confirmed the diagnosis Stevens-Johnson syndrome. The pharmacovigilance declaration concluded that Stevens-Johnson syndrome was secondary to capecitabine according to chronological and bibliographic data. The patient died of respiratory distress. ConclusionStevens-Johnson syndrome is a rare and serious complication that can occur, rarely, in patients treated with capecitabine. Our case is the 5th case of capecitabine-induced SJS that has been reported in the literature since 2008.

Switching from FOLFIRI plus cetuximab to FOLFIRI plus bevacizumab based on early tumor shrinkage in RAS wild-type metastatic colorectal cancer: A phase II trial (HYBRID).

Long-term anti-EGFR antibody treatment increases the risk of severe dermatologic toxicities. This single-arm, phase II trial aimed to investigate the strategy of switching from cetuximab to bevacizumab in combination with FOLFIRI based on early tumor shrinkage (ETS) in patients with RAS wild-type metastatic colorectal cancer (mCRC). Radiologic assessment was performed to evaluate ETS, defined as ≥20% reduction in the sum of the largest diameters of target lesions 8 weeks after the introduction of FOLFIRI plus cetuximab. ETS-negative patients switched to FOLFIRI plus bevacizumab, whereas ETS-positive patients continued FOLFIRI plus cetuximab for eight more weeks, with a switch to FOLFIRI plus bevacizumab thereafter. The primary endpoint was progression-free survival. This trial was prematurely terminated due to poor accrual after a total enrollment of 30 patients. In 29 eligible patients, 7 were ETS-negative and 22 were ETS-positive. Two ETS-negative patients and 17 ETS-positive patients switched to FOLFIRI plus bevacizumab 8 weeks and 16 weeks after initial FOLFIRI plus cetuximab, respectively. Median progression-free and overall survival durations were 13.4 and 34.7 months, respectively. Six (20%) patients experienced grade ≥3 paronychia, which improved to grade ≤2 by 18 weeks. Grade ≥3 acneiform rash, dry skin, and pruritus were not observed in any patients. Our novel treatment strategy delivered acceptable survival outcomes and reduced severe dermatologic toxicities.

Dermatologic toxicity associated with targeted and immunotherapies in stage-IV non-small cell lung cancer patients: A 14-year cohort

Dermatologic toxicity associated with targeted and immunotherapies in stage-IV non-small cell lung cancer patients: A 14-year cohort

Dermatologic Effects of Selumetinib in Pediatric Patients with Neurofibromatosis Type 1: Clinical Challenges and Therapeutic Management.

Background: Plexiform neurofibromas (pNFs) are benign neoplasms, primarily originating from Schwann cells, posing challenges in patients with type 1 neurofibromatosis (NF1) due to pain, disfigurement, compression of vital structures and potential for malignancy. Selumetinib, a MEK1/2 inhibitor, has shown promising results in treating inoperable pNFs, with clinical trials demonstrating tumor volume reduction and improved patient-reported outcomes. Despite its efficacy, dermatologic toxicities may impact the quality of life and treatment adherence. Evaluating the frequency and spectrum of such effects is crucial for effective management. Methods: In a four-year retrospective and prospective study, pediatric NF1 patients with symptomatic, inoperable plexiform neurofibromas (pNFs) were treated with selumetinib. Eligibility criteria included significant morbidity, pNF size exceeding 3 cm or surgical inoperability, and performance status >70%. Hematological, liver, lung and cardiac assessments established baseline health. Selumetinib, orally administered at 25 mg/m2 twice, was administered for two years unless a response warranting extension occurred. Cutaneous AEs were documented and graded by severity according to CTCAE v5.0, with evaluations every three to six months. The impact on symptoms and pNF size was systematically recorded, and biopsies characterized histopathological features in those patients requiring surgery. Results: Twenty patients were enrolled, with an average age at therapy initiation of 11.6 years. Cutaneous side effects were common, with all patients experiencing at least one and a median of two per patient. Xerosis, paronychia and acneiform rash were prevalent. Notably, pre-pubertal individuals were more susceptible to xerosis. Acneiform rash had a higher incidence in older patients and those with skin phototypes II and III. Successful management involved tailored approaches, such as clindamycin for acneiform rash and topical agents for paronychia. Hair abnormalities, including color changes and thinning, occurred, with female patients at higher risk for the latter. Paronychia presented challenges, necessitating various interventions, including surgical approaches. AEs led to treatment suspension in 20% of patients, with tumor rebound observed in 75%. Conclusions: According to our experience, successful management of selumetinib-induced cutaneous AEs requires tailored strategies including surgery. AEs might indirectly determine pNF regrowth due to therapy suspension. We thus emphasize the pivotal role of addressing cutaneous reactions for effective selumetinib management in pediatric patients.

Dermatological toxicity in the treatment of malignant tumors in children: A review

Modern antitumor drugs have high antitumor activity. But only a number of them realize their antitumor effect in a targeted manner with minimal manifestations of concomitant toxicity. Damage to the skin and mucous membranes as part of the toxic effects of chemotherapy not only reduces the quality of life of patients, but can lead to disruption of the patient’s nutritional status, infection, and generalization of the infectious process with the development of sepsis. This review describes the major drugs that have dermatological toxicity, the main clinical variants of dermatological toxicity, methods for their prevention and treatment.

Achilles' Heel of currently approved immune checkpoint inhibitors: immune related adverse events.

Immunotherapy has revolutionized the cancer treatment landscape by opening up novel avenues for intervention. As the use of immune checkpoint inhibitors (ICIs) has exponentially increased, so have immune-related adverse events (irAEs). The mechanism of irAEs may involve the direct damage caused by monoclonal antibodies and a sequence of immune responses triggered by T cell activation. Common side effects include dermatologic toxicity, endocrine toxicity, gastrointestinal toxicity, and hepatic toxicity. While relatively rare, neurotoxicity, cardiotoxicity, and pulmonary toxicity can be fatal. These toxicities pose a clinical dilemma regarding treatment discontinuation since they can result in severe complications and necessitate frequent hospitalization. Vigilant monitoring of irAEs is vital in clinical practice, and the principal therapeutic strategy entails the administration of oral or intravenous glucocorticoids (GSCs). It may be necessary to temporarily or permanently discontinue the use of ICIs in severe cases. Given that irAEs can impact multiple organs and require diverse treatment approaches, the involvement of a multidisciplinary team of experts is imperative. This review aims to comprehensively examine the pathogenesis, clinical manifestations, incidence, and treatment options for various irAEs.