Risk Of Cutaneous Adverse Events Research Articles

CACA guidelines for holistic integrative management of anticancer treatment - induced cutaneous adverse events

PurposeThe skin and mucous membrane of cancer patients can be directly or indirectly impaired during the treatment of cancers, bringing about not physical but also psychological damages to cancer patients. A practical guideline is of great significance to improve the quality of life for patients suffered from cutaneous adverse events.MethodsThis guideline was generated based on up-to-date evidence and the consensus of experts specialized in dermatology.ResultsThe current guideline include the baseline screening of skin and mucosal membranes, the manifestations of injuries on skin, mucosa and appendages, along with the treatment of them. The causal anti-tumor management include chemotherapy, radiotherapy, immune therapy and surgery.ConclusionThis guideline can be helpful to reduce the risk of cutaneous adverse events during anti-cancer treatment and improve the quality of life of patients suffered from these adverse events.

Incidence of Cutaneous Adverse Events With Phosphoinositide 3-Kinase Inhibitors as Adjuvant Therapy in Patients With Cancer

ImportanceThe phosphoinositide 3-kinase (PI3K) pathway is among the most frequently activated pathways in human cancers. As the use of PI3K inhibitors for cancer treatment grows, there is increasing need for understanding the cutaneous effects associated with these therapies.ObjectiveTo systematically review the published literature reporting incidence of cutaneous adverse events with PI3K inhibitors and to provide pooled incidence estimates using meta-analysis.Data SourcesThis systematic review and meta-analysis was conducted using the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) reporting guidelines. The literature search concerned entries through September 2021 in the following sources: PubMed, Cochrane registry, ClinicalTrials.gov, and evidence from the NHS UK and Trip medical database. To analyze PI3K inhibitors’ cutaneous adverse events incidence, only randomized clinical trials (RCTs) were considered. The search strategy used the following keywords: (prevalence OR incidence OR epidemiology) and (phosphoinositide 3 kinase inhibitors OR PI3K inhibitors). No language restriction was applied. Analysis was conducted on July 1, 2022.Study SelectionStudies included phase 2 and phase 3 RCTs that reported incidence of cutaneous adverse events associated with use of PI3K inhibitors.Data Extraction and MeasuresData extracted included sex, medication name and class, sample size, rash incidence, and grade. The bias risk was assessed by the Cochrane tool for risk of bias assessment in RCTs.Main Outcomes and MeasuresThe primary outcome was incidence of PI3K inhibitor cutaneous adverse events (with 95% CIs) among the overall population and among subgroups. Between-study heterogeneity was assessed using the I2 statistic.ResultsThe analysis found the incidence of PI3K inhibitor cutaneous events of any grade to be 29.30% in the intervention group, translating to a pooled odds ratio (OR) for incidence of cutaneous adverse events of any grades of 2.55 (95% CI, 1.74-3.75). Incidence of severe grade (grade ≥3) of rash in the intervention group was estimated to be 6.95%, yielding a pooled Peto OR of 4.64 (95% CI, 2.70-7.97). Subgroup analyses revealed that the incidence of severe cutaneous adverse events (grade ≥3) was higher with the use of Pan-class-1 PI3K inhibitors (OR, 6.67; 95% CI, 4.28-10.38) than isoform-selective PI3K inhibitors (OR, 6.37; 95% CI, 3.25-12.48).Conclusions and RelevanceThis systematic review and meta-analysis identified an overall incidence of PI3K inhibitor cutaneous adverse events of any grade to be 29.30% with a pooled OR of 2.55; (95% CI, 1.74-3.75). These findings clarify the risk of cutaneous adverse events associated with this important class of anticancer therapies.

Risk of cutaneous adverse events in cancer patients treated with phosphatidylinositol-3-kinase inhibitors: A systematic review and meta-analysis of randomized controlled trials.

Cutaneous adverse effects (AEs) are common following the phosphoinositide-3-kinase (PI3K) inhibitors treatment. We aim to estimate the incidence and risk of PI3K inhibitor-related cutaneous AEs. The protocol was submitted to the PROSPERO registry. We searched ClinicalTrials.gov and international databases up to July 29, 2022. Meta-analysis was conducted by using risk ratios (RRs) with 95% confidence intervals (CIs). Fourteen randomized controlled trials (RCTs) comprising 3877 patients were analyzed in this study. Compared with control arms, PI3K inhibitors showed a significant increase in the risk of all-grade rash, high-grade rash, and serious rash events (RR 2.29, 95% CI 1.58-3.31, p < 0.00001; RR 9.34, 95% CI 4.21-20.69, p < 0.00001; RR 5.11, 95% CI 2.11-12.36, p=0.0003). The overall incidences of all-grade rash and high-grade rash were 26.2% (592/2257) and 4.4% (66/1487). Subgroup analyses of all-grade rash according to cancer types and PI3K inhibitor assignations identified the significant associations. PI3K inhibitors also significantly increased the risk of pruritus and dry skin (RR 1.63, 95% CI 1.14-2.33, p=0.007; RR 3.34, 95% CI 2.30-4.85, p < 0.00001), with incidences of 13.4% (284/2115) and 9.8% (141/1436) in the treatment group. There is a significantly increased risk of some cutaneous AEs in patients using PI3K inhibitors. Advance intervention is recommended in case of severe and life-threatening events. Further research is required to investigate the risk factors and pathogenesis.

Low Body Weight as a Risk Factor for Apalutamide-related Cutaneous Adverse Events.

Therapeutic strategies for prostate cancer are currently undergoing a paradigm shift due to the advent of next-generation androgen receptor inhibitors. Among these inhibitors, apalutamide is regarded as a key drug because of its effectiveness. However, risk factors for and the timing of the onset of apalutamide-related cutaneous adverse events remain unclear. Therefore, the present study investigated key risk factors for and timing of the onset of apalutamide-related cutaneous adverse events. Sixty-two Japanese patients with non-metastatic castration-resistant prostate cancer treated with 240 mg/day of apalutamide were enrolled in the present study. Twenty-four patients (38.7%) developed cutaneous adverse events. Multivariable logistic regression analysis of age, height, and body weight identified body weight as a significant predictive factor for the incidence of cutaneous adverse events (p=0.019). When the mean body weight of patients (63.80 kg) was set as the cut-off value, the Kaplan-Meier analysis revealed that the risk of cutaneous adverse events was significantly increased in those with a body weight <63.8 kg (p=0.003, the log-rank test). The analysis also showed that cutaneous adverse events developed within the first 6 months regardless of body weight. A lower body weight is a significant risk factor for apalutamide-related cutaneous adverse events and their onset is within 6 months of initiation of therapy.

Dermatological Complications After Solid Organ Transplantation.

Organ transplant recipients (OTRs) are a population at high risk for cutaneous adverse events. Their early recognition and appropriate treatment is an important component of the clinical management of OTRs and should be optimally dealt with by dermatologists working in the context of a transplant dermatology clinic. Skin examination should be a standard procedure before performing organ transplantation to assess conditions which may be difficult to manage after the transplant procedure has been performed or which may represent a contraindication to transplantation, e.g., malignant melanoma. It also offers an opportunity to educate patients on skin care after organ transplantation. Skin infections can occur at any time after organ transplantation and include viral, bacterial, and fungal opportunistic infections. The risk of reactivation of latent viruses, such as varicella-zoster virus (VZV) and cytomegalovirus (CMV), is high. Bacterial infections are frequent and may be caused by unusual agents such Actinomyces, Mycobacteria, Legionella, or Nocardia. A large spectrum of fungal infections may occur, ranging from superficial (e.g., dermatophytes) to deeper and more severe ones (Alternaria, Aspergillus, Cryptococcus, Histoplasma). Drug-related idiosyncratic reactions usually occur early after the introduction of the causative drug, e.g., hypersensitivity reaction to azathioprine. On the long-term run, cutaneous effects due to cumulative drug toxicity, e.g., sebaceous hyperplasia from cyclosporine, may appear. Rare immunologically driven inflammatory reactions may occur in OTRs such as GVH or autoimmune disease. Tumors are particularly frequent. Kaposi's sarcoma, associated with persistent human herpes virus 8 (HHV8) infection, and cutaneous anaplastic large-cell lymphoma (ALCL) occur early after transplantation. Other cancers, such as nonmelanoma skin cancer (NMSCs), associated with persistent human papillomavirus (HPV) infections, malignant melanoma, Merkel cell carcinoma, or adnexal tumors, manifest later with an incidence which is much higher than observed in the general population. The incidence increases further after a first NMSC occurs.

Risk of cutaneous adverse events with febuxostat treatment in patients with skin reaction to allopurinol. A retrospective, hospital-based study of 101 patients with consecutive allopurinol and febuxostat treatment

ObjectiveTo investigate the cutaneous tolerance of febuxostat in gouty patients with skin intolerance to allopurinol. MethodsWe identified all gouty patients who had sequentially received allopurinol and febuxostat in the rheumatology departments of 4 university hospitals in France and collected data from hospital files using a predefined protocol. Patients who had not visited the prescribing physician during at least 2 months after febuxostat prescription were excluded. The odds ratio (OR) for skin reaction to febuxostat in patients with a cutaneous reaction to allopurinol versus no reaction was calculated. For estimating the 95% confidence interval (95% CI), we used the usual Wald method and a bootstrap method. ResultsIn total, 113 gouty patients had sequentially received allopurinol and febuxostat; 12 did not visit the prescribing physician after febuxostat prescription and were excluded. Among 101 patients (86 males, mean age 61±13.9 years), 2/22 (9.1%) with a history of cutaneous reactions to allopurinol showed skin reactions to febuxostat. Two of 79 patients (2.5%) without a skin reaction to allopurinol showed skin intolerance to febuxostat. The ORs were not statistically significant with the usual Wald method (3.85 [95% CI 0.51–29.04]) or bootstrap method (3.86 [95% CI 0.80–18.74]). ConclusionThe risk of skin reaction with febuxostat seems moderately increased in patients with a history of cutaneous adverse events with allopurinol. This moderate increase does not support the cross-reactivity of the two drugs.

Association of sirolimus adverse effects with m-TOR, p70S6K or Raptor polymorphisms in kidney transplant recipients

The mammalian target of rapamycin (m-TOR) inhibitor sirolimus is an immunosuppressive drug used in kidney transplantation. m-TOR binds with Raptor and phosphorylates p70S6 kinase, a protein involved in numerous cell signalling pathways. We examined the association of candidate polymorphisms in m-TOR, Raptor and p70S6K, sirolimus dose and exposure, and other time-independent as well as time-dependent covariates, with sirolimus-induced adverse events in kidney transplant recipients. This study included a first group of 113 patients, switched from a calcineurin inhibitor to sirolimus, and a validation group of 66 patients from another clinical trial, with the same immunosuppressive regimen. The effects of gene polymorphisms and covariates on the total cholesterol, LDL cholesterol, triglycerides, haemoglobin, cutaneous adverse events, oedemas and infections were studied using multilinear regression, or logistic regression imbedded in linear mixed-effect models. An m-TOR variant haplotype was significantly associated with a decrease in haemoglobin levels in the two populations of patients (discovery group: β=-0.82 g/dl, P=0.0076; validation group: β=-1.58 g/dl, P=0.0308). Increased sirolimus trough levels were significantly associated with increased total cholesterol levels (discovery group: β=0.02 g/l, P<0.0001; validation group: β=0.02 g/l, P=0.0002) and triglyceride levels (discovery group: β=0.02 g/l, P=0.0059; validation group: β=0.05 g/l, P=0.0370). Sirolimus trough levels were also associated with an increased risk for cutaneous adverse events [odds ratio=1.97, 95% confidence interval (1.32-1.94), P=0.0009] and oedemas [odds ratio=1.16, 95% confidence interval (1.03-1.30), P=0.01342] in the discovery group, but this was not confirmed in the validation group. These results provide evidence of an association between an m-TOR haplotype and a decrease in haemoglobin in renal transplant recipients.

Toxicogenomics of nevirapine-associated cutaneous and hepatic adverse events among populations of African, Asian, and European descent

Nevirapine is widely prescribed for HIV-1 infection. We characterized relationships between nevirapine-associated cutaneous and hepatic adverse events and genetic variants among HIV-infected adults. We retrospectively identified cases and controls. Cases experienced symptomatic nevirapine-associated severe (grade III/IV) cutaneous and/or hepatic adverse events within 8 weeks of initiating nevirapine. Controls did not experience adverse events during more than 18 weeks of nevirapine therapy. Cases and controls were matched 1: 2 on baseline CD4 T-cell count, sex, and race. Individuals with 150 or less CD4 T cells/μl at baseline were excluded. We characterized 123 human leukocyte antigen (HLA) alleles and 2744 single-nucleotide polymorphisms in major histocompatibility complex (MHC) and drug metabolism and transport genes. We studied 276 evaluable cases (175 cutaneous adverse events, 101 hepatic adverse events) and 587 controls. Cutaneous adverse events were associated with CYP2B6 516G→T (OR 1.66, all), HLA-Cw*04 (OR 2.51, all), and HLA-B*35 (OR 3.47, Asians; 5.65, Thais). Risk for cutaneous adverse events was particularly high among Blacks with CYP2B6 516TT and HLA-Cw*04 (OR 18.90) and Asians with HLA-B*35 and HLA-Cw*04 (OR 18.34). Hepatic adverse events were associated with HLA-DRB*01 (OR 3.02, Whites), but not CYP2B6 genotypes. Associations differed by population, at least in part reflecting allele frequencies. Among patients with at least 150 CD4 T cells/μl, polymorphisms in drug metabolism and immune response pathways were associated with greater likelihood of risk for nevirapine-related adverse events. Results suggest fundamentally different mechanisms of adverse events: cutaneous, most likely MHC class I-mediated, influenced by nevirapine CYP2B6 metabolism; hepatic, most likely MHC class II-mediated and unaffected by such metabolism. These risk variants are insensitive for routine clinical screening.