Severity Of Rash Research Articles

Randomized, open-label trial evaluating the preventive effect of tetracycline on afatinib induced-skin toxicities in non-small cell lung cancer patients

Afatinib has shown long progression free survival and improvement in quality of life in advanced Non-Small Cell Lung Cancer (NSCLC) patients. Although afatinib causes acneiform rash, it can be manageable. Tetracyclines are usually used to treat it; nonetheless, there is no trial that evaluates their prophylactic efficacy on afatinib induced-skin toxicities (AIST). This open-label, randomized, controlled trial assessed the preventive effect of tetracycline for reducing afatinib-skin toxicities in NSCLC patients receiving afatinib 40 mg/day. Patients were randomly assigned to receive pre-emptive treatment with tetracycline 250 mg every 12h for 4 weeks or not. Reactive treatment in both groups included general dermatological recommendations such as use of skin moisturizers, sunscreen and topical steroids, according to toxicity severity. All patients were blindly monitored for skin toxicities by an expert dermatologist at the start of treatment with afatinib (day 0), weeks 2 and 4 of treatment. The protocol is registered on clinicaltrials.gov (NCT01880515). We included 90 patients, no differences were found in clinical and dermatological baseline characteristics. Rash incidence of any grade, and grade ≥2 was less frequent in the pre-emptive arm vs. the control arm (44.5 vs. 75.6%, RR 0.4 [95% CI 0.17-0.99], p=0.046 and 15.6 vs. 35.6%, RR 0.35 [95% CI, 0.12-0.91], p=0.030, respectively). No difference was found in paronychia, xerosis, mucositis, folliculitis, and skin fissure. No adverse event was associated with tetracycline. Neither rash nor pre-emptive tetracycline impacted on response rate, progression-free or overall survivals. Pre-emptive tetracycline was well tolerated and reduced the rash incidence and severity associated with afatinib in more than 60%.

CA-SSR1 Polymorphism in Intron 1 of the EGFR Gene in Patients with Malignant Tumors Who Develop Acneiform Rash Associated with the Use of Cetuximab.

Background and ObjectiveEpidermal growth factor receptor (EGFR) inhibitors are not equally effective in all cancer patients. One potential clinical factor that could help in selecting patients who may benefit from treatment with cetuximab is acneiform rash, which correlates with the clinical response to EGFR inhibitors. Some previous studies have suggested that the tendency to develop rash may depend on polymorphisms in the EGFR gene. In this investigation, the association of degree of CA dinucleotide polymorphism with skin rash and cetuximab therapy outcome was examined.MethodsThe study included 60 patients treated with cetuximab. For each patient, the severity of acneiform rash was assessed, and the type of polymorphism was determined by genotyping. Associations between genotypes, the acneiform rash, and response to treatment were determined by using the chi-square test and Spearman’s rank correlation. The cutoffs S ≤ 17(CA), L > 17(CA), n(CA) ≤ 35, and n(CA) > 35 were tested, as well as the sum of the two allele repetitions.ResultsA correlation was found between body surface area covered by rash and the sum of the two allele repetitions (p = 0.030). No statistically significant relationship between genotype and response to treatment was observed. However, in patients who have had partial remission, we noticed a higher incidence of polymorphism, with less CA dinucleotide repetitions and early onset of rash.ConclusionA correlation between genotype and severity of rash was observed. That is, the severity of rash decreased with an increased number of CA repetitions.

Preemptive therapy of cetuximab-induced skin rash using doxycycline, sunscreen, hydrocortisone, and moisturizer in colorectal and head and neck cancer patients.

TPS796 Background: Toxicities associated with the use of cetuximab include infusion reactions, dermatologic toxicity and electrolyte disturbances. Of these, skin toxicity including acneiform rash, dry skin and fissuring, paronychial inflammation, infectious sequelae and hypertrichosis occur most commonly, with acneiform rash developing in 76-88% of patients. These skin toxicities are rarely life-threatening, but they impact the quality of life of patients receiving therapy and directly affect adherence. The purpose of this study is to determine if preemptive therapy with doxycycline, sunscreen, hydrocortisone 1% cream, and moisturizer will reduce the incidence and severity of > grade 2 acneiform rash according to CTCAE v.4 in patients with colorectal and head and neck cancer receiving therapy with cetuximab. Methods: This is a single-institution, prospective, open-label, randomized study of 100 patients with colorectal and head and neck cancer receiving cetuximab in the locally advanced or metastatic setting. Those randomized to preemptive therapy will receive doxycycline 100 mg twice daily, sunscreen SPF 30, hydrocortisone 1% cream, and moisturizer beginning three days prior to the first dose of cetuximab for a duration of 8 weeks. Those randomized to standard of care will receive treatment of skin toxicity per national guidelines and treating physician discretion. Objectives are to evaluate the incidence of cetuximab-induced rash, compare the severity of cetuximab-induced rash between the preemptive treatment group and the standard care group, and monitor the toxicity of the preemptive therapy. Secondary objectives include quality of life, adherence rates, disease-specific outcomes, and survival. Patients will be evaluated at enrollment, 3 weeks into treatment and at the end of treatment for adherence, side effects and quality of life. They will be followed for up to two years for treatment outcomes and survival. With alpha of 0.05 and a power of 80%, we will be able to detect if the incidence of skin rash differs by 24% between the two groups using a two-sample one-sided binomial test. As of September 2014, 15 of 100 patients have been enrolled. Clinical trial information: NCT01874860.

Study of Hepatic Dysfunction in Patientsinfected with Dengue Virus

Dengue fever is a fatal infection affecting the lives of the patients and this study was designed to further explore its pathological effects. A total of 200 consecutives of dengue viral infection were included in this prospective descriptive study conducted at the Department of Pathology, University of Veterinary and Animal Sciences, Lahore from October, 2009 to September, 2010. A special proforma was designed to collect all the relevant clinical information from each patient. All the strip positive cases of dengue virus were further confirmed by performing IgM capture ELISA and then analyzed for hepatic impairment through liver function tests including serum bilirubin, serum alkaline phosphatase, serum ALT and AST. The results were then gathered and analyzed. The already existing liver diseases like hepatitis A, B, C, E and inherited liver disorders were not included in the study. Total number of patients included in study with Dengue IgM +ve were 200. Out of 200 cases 130 were male and 70 were females. The patients were categorized into two classes according to severity of sign symptoms like puerperal rash on the body. The classes are dengue fever (DF) and dengue hemorrhagic fever (DHF). The total number of DF cases was 28.50% (57/200) and number of DHF cases was 71.50% (143/200). The patients of DHF group were found to have more liver derangement that is 90.20% (128/200) while the patients belonging to DF group were at a less risk for impairment of liver function that is 9.80% (15/200). The patients with dengue hemorrhagic fever are more prone to have liver enzyme derangement and it has a direct relation with the titer IgM in the body of patients infected with dengue virus. The liver enzyme which are found to be more raised are serum ALT and AST while serum alkaline phosphatase and serum bilirubin are not markedly raised.

Two-dose varicella vaccine effectiveness and rash severity in outbreaks of varicella among public school students.

Universal 2-dose varicella vaccination was recommended in 2006 to further reduce varicella disease burden. This study examined 2-dose varicella vaccine effectiveness (VE) and rash severity in the setting of school-associated varicella outbreaks. A case control study was conducted from January 2010 to May 2011 in all West Virginia public schools. Clinically diagnosed cases from varicella outbreaks were matched with classmate controls. Vaccination information was collected from school, health department and healthcare provider immunization information systems. Among the 133 cases and 365 controls enrolled, VE against all varicella was 83.2% [95% confidence interval (CI): 69.2%-90.8%] for 1-dose of varicella vaccine and 93.9% (95% CI: 86.9%-97.1%) for 2-dose; the incremental VE (2-dose vs. 1-dose) was 63.6% (95% CI: 32.6%-80.3%). In preventing moderate/severe varicella, 1-dose varicella vaccine was 88.2% (95% CI: 72.7%- 94.9%) effective, and 2-dose vaccination was 97.5% (95% CI: 91.6%-99.2%) effective, with the incremental VE of 78.6% (95% CI: 40.9%-92.3%). One-dose VE declined along with time since vaccination (VE = 93.0%, 88.0% and 81.8% in <5, 5-9 and ≥ 10 years after vaccination, P = 0.001 for trend). Both 1- and 2-dose breakthrough cases had milder rash than unvaccinated cases (<50 lesion: 24.6%, 49.1% and 70.0% in unvaccinated, 1-dose and 2-dose cases, P < 0.001), and no severe disease was found in 2-dose cases. Two-dose varicella vaccination is highly effective and confers higher protection than a 1-dose regimen. High 2-dose varicella vaccination coverage should maximize the benefits of the varicella vaccination program and further reduce varicella disease burden in the United States.

ARIZONA study: is the risk of post-herpetic neuralgia and its burden increased in the most elderly patients?

BackgroundIn a context of change in the demographic profile of the older population, to identify an age threshold for increased risk and burden of herpes zoster (HZ) in 70+ patients.MethodsPost hoc analysis of the 12-month French nationwide prospective observational ARIZONA cohort study. HZ was assessed by means of the following validated questionnaires: Neuropathic Pain Symptom Inventory (NPSI), Zoster Brief Pain Inventory (ZBPI), Short-Form health survey (SF-12), and Hospital Anxiety and Depression Scale (HADS).Results644 general practitioners included 1,358 volunteer patients with acute HZ in the ARIZONA study; 609 patients (45%) were 70+. In 70+ patients, age did not increase rash severity or HZ-related pain intensity at diagnosis, but increased by 64% the frequency of ophthalmic zoster (from 5.5% in 70–74 years age-group to 9.0% in 85+ patients, p = NS). Age was significantly associated with low physical health as assessed by the SF-12 Physical Component Summary (SF-12 PCS) score and bad mood as assessed by the HADS depression score (p < 0.001). Within the year following HZ, post-herpetic neuralgia (PHN) was systematically but not significantly more frequent in 85+ patients than in the 70–74, 75–79, or 80–84 years age-groups (19.0% vs. 13.3%/15.3%/11.6% at month 3; 15.1% vs. 7.3%/11.0%/12.2% at month 6; 15.2% vs. 6.0%/8.0%/6.0% at month12, respectively). SF-12 PCS and HADS depression scores improved from day 0 to month 12 in all patients (p < 0.001). 85+ patients were more impaired than younger patients (p < 0.001), but without clear difference according to PHN.ConclusionsThis study did not show in 70+ patients a clear and significant age threshold at which disease burden increased, although for some domains the impact seemed higher among the oldest patients; the cut-off of 70 years remains thus relevant for clinical and epidemiological studies. However, at individual level, assessment of the burden of HZ and HZ-related pain appears necessary to improve management and prevent functional decline in the most vulnerable 70+ patients.Electronic supplementary materialThe online version of this article (doi:10.1186/1471-2334-14-529) contains supplementary material, which is available to authorized users.

Prophylactic Treatment for Rash Induced By Egfr Inhibitor Improves Rash Without Compromising on Efficacy the Pancanadian Rash Trial: a Randomized Phase III Trial in Nsclc

ABSTRACT Aim: Erlotinib is approved for the treatment of patients with metastatic NSCLC following progression of chemotherapy as well for patients who harbour an EGFR mutation. Rash may limit exposure to drug and compromise efficacy. The objective of our study was to determine the proper treatment of EGFR inhibitor-induced rash in the 2nd line or greater setting. A secondary objective was to prospectively observe the relationship between rash and survival and to see if intervention for rash was detrimental. Methods: 150 patients metastatic NSCLC to be started on erlotinib in 2nd/3rd line were randomized to : Arm 1: Prophylactic: Minocycline (150 po bid 4 weeks) on day 1 of erlotinib Arm 2: Reactive: Topical clindamycin plus hydrocortisone +/- minocycline upon rash occurrence Arm 3: Control: No treatment of rash unless severe (Grade 3) Results: Although not statistically significant, previous results showed Arms 1 and 2 had the longest overall survival from randomization. Arm 1: 7.6 months, Arm 2: 8.0 months, Arm 3: 6.0 months p = 0.38 Median survival was analyzed for the 150 patients for worst grade of rash experienced. Survival was significantly longer in patients who experienced severe or moderate rash (Grade 3 or 2) versus mild or no rash (Grade 0/1). Grade 3 rash: 11.4 months, Grade 2 rash: 10.1 months, Grade0/1 rash: 5.5 months p = 0.0093 Porphylactic minocycline in Arm 1 increased Grade 2 and decreased Grade 3 rash significantly. p= 0.3. Number and Percent of Patients with Worst Rash Grade for each Treatment Arm Arm RashGrade 0/1 N% RAsh Grade 2 N% RAsh Grade 3 N% Total 1 25 (50%) 20 (40%) 5 (9.5%) 50 2 28 (46%) 15 (30%) 7 (14.3%) 50 3 28 (46%) 5 (10%) 17 (34.1%) 50 Conclusions: In this prospective trial, a relationship between severity of rash and survival was seen. Moderate (Grade2) and severe (Grade3) rash demonstrated a superior overall survival compared to no or mild (Grade 1) rash. Prophylactic minocycline reduced the incidence of severe Grade 3 rash but increased the moderate Grade2 rash. Prophylactic minocyline should be considered in patients upon initiation of erlotinib therapy. Disclosure: All authors have declared no conflicts of interest.

Managing skin toxicities related to panitumumab

Dermatologic toxicities from targeted agents such as panitumumab can interfere with cancer treatment. We sought to evaluate the rash assessment and management in a consecutive patient cohort who received panitumumab for colorectal cancer treatment. This was a retrospective chart review. Skin toxicity, consisting of papulopustular rash, was experienced by 32 of 34 patients. The majority (85%) developed the rash by the end of the second infusion cycle. Patients presented with a mild (41%), moderate (38%), and severe (21%) rash, and progressed to an extensive rash without appropriate treatment. A grading system was used for 65% of patients to document severity. Small sample size limited power in analysis. Rash severity had to be inferred based on rash description and management in 11 of the patients. Dermatologic toxicities related to panitumumab are common; however, the way they are reported and managed varies among physicians. To prevent progression, toxicities must be assessed and treated early and aggressively, according to severity grading. Dermatologists could aid oncologists in choosing the best management strategies.

Postherpetic neuralgia: Therapeutic and prophylactic aspects and pregabalin therapy

Postherpetic neuralgia (PHN) is one of the most common and persistent chronic pain syndromes caused by chickenpox virus affecting the peripheral and central nervous systems. PHN is a typical neuropathic pain resulting from injury or dysfunction of the somatosensory system whose development involves a few mechanisms. Elderly people are more prone to PHN, which is associated with the weakened immune system. Treatment of shingles cannot completely prevent subsequent neuralgia; however, some drugs can reduce its manifestations. The diagnosis of PHN is largely based on the duration of pain after rash onset. However, it is difficult to estimate the real rate of PHN development because there is neither consensus of opinion on this issue nor common criteria for pat duration (1 to 6 months, as shown by different data). The significant factors that may predispose to PHN are older age, female gender, and acute herpes zoster indicators, such as pain intensity, the severity of herpetic rash and infectious manifestations. Pain syndrome in PHN can reach a high intensity level, accompanied by the development of chronic fatigue, depression, and loss of social skills. There are several types of pain in PHN: constant, paroxysmal and allodynia, which are due to different pathophysiological mechanisms. Variability in the clinical manifestations of PHN may underlie the inadequate efficacy of one or other drug. The treatment of PHN poses definite difficulties. About 40-50% of patients continue to suffer from pain despite the fact that the multitude of currently available therapies is performed. Pregabalin, whose high efficacy and advantages in the treatment of pain in PHN are demonstrated in numerous studies, is one of the most effective first-line drugs for PHN. In-depth analysis suggests that inadequately low doses of pregabalin are frequently used in the treatment of PHN, which may lead to an insufficient analgesic effect.

Impact of patient ethnicity on the metabolic and immunologic effects of PI3K-mTOR pathway inhibition in patients with solid tumor malignancies.

Inhibition of the phosphatidylinositol 3-kinase (PI3K)/mammalian target of rapamycin (mTOR) pathway is associated with metabolic and immunologic perturbations that impact drug tolerability. Here, we studied whether PI3 kinase/mTOR pathway inhibitors are associated with greater metabolic impact and decreased tolerability in Asian patients. A retrospective analysis was conducted of consecutive patients with advanced malignancies treated on phase 1 trials of PI3K/mTOR inhibitors. Adverse events related to PI3K/mTOR inhibition, fasting plasma glucose (FPG), insulin, and c-peptide levels, hemoglobin A1c (HgbA1c), and T cell subsets were prospectively collected. Mann-Whitney and Chi-square tests were used to compare continuous and categorical variables, respectively, between Asian and Caucasian patients. A total of 103 patients (31 Asian; 72 Caucasian) were treated consecutively across five clinical trials. Baseline age, gender distribution, and metabolic parameters were comparable with the exception of lower median body mass index (BMI) in Asian patients (23.0 vs. 24.8 kg/m(2), p = 0.024). There were no differences in drug tolerability, adherence, or duration of therapy. Asian patients experienced a higher incidence of grade ≥ 2 hyperglycemia (37.5 vs. 18.1%, p = 0.03), and greater increases in FPG, HgbA1c, and insulin resistance. No differences in incidence or severity of mucositis, rash, or pneumonitis were observed. Drug effects on neutrophils, lymphocytes, and T cell subsets were similar. PI3K/mTOR inhibitors have greater glycemic impact in Asian patients, despite similar baseline metabolic parameters, comparable dose intensity, and a lower median BMI. Further studies are warranted to explore the mechanisms underlying these differences and optimize dosing in Asian patients.

The correlation between the severity of cetuximab-induced rash and clinical outcome for patients with head and neck carcinoma treated with chemoradiotherapy (CRT) plus cetuximab: The RTOG experience.

6025 Background: To evaluate the severity of cetuximab-induced rash and its correlation with clinical outcome and late skin toxicity. Methods: The analysis included patients who received definitive...

The relationship between rash, tumour KRAS mutation status and clinical and quality of life outcomes in patients with advanced colorectal cancer treated with cetuximab in the NCIC CTG/AGITG CO.17

Background. The NCIC CTG/AGITG CO.17 trial demonstrated that cetuximab monotherapy improved overall and progression-free survival (OS and PFS) in patients previously treated for advanced colorectal cancer. A strong relationship was observed between benefit from cetuximab and development of rash. In this analysis, the association of rash and benefit from cetuximab is explored and presented by KRAS mutation status.Material and methods. Rash was graded by NCI CTC 2.0 criteria. Landmark analysis was performed by excluding patients who died or dropped out within 28 days and then grouping by worst grade of rash experienced by day 28. Multivariate Cox models were conducted separately for patients with KRAS wild-type (WT) tumours and KRAS mutated (MUT) tumours. CO.17 primary outcome was OS.Results. Development of grade 2 + rash on cetuximab was associated with a trend towards increased OS (HR 0.61 with 95% CI 0.36–1.02 and p = 0.06) and PFS (HR 0.68 with 95% CI 0.45–1.03 and p = 0.07) as compared to grade 0/1 rash in patients with WT tumours. In patients with WT tumours on cetuximab both grade 0/1 and grade 2 + rash were associated with increased PFS (HR 0.57 95% CI 0.38–0.86; p = 0.008; and HR 0.32 95% CI 0.21–0.49; p < 0.0001) respectively, in comparison with best supportive care (BSC). Only development of grade 2 + rash on cetuximab was associated with increased OS (HR 0.52 with 95% CI 0.34–0.80 and p = 0.003) in comparison with BSC. No significant difference was found in OS or PFS among patients on cetuximab with MUT tumours with either rash grade as compared to BSC. No consistent trend was observed for the association of severity of rash and quality of life (QoL).Conclusion. As all patients with WT tumours benefitted to some extent from cetuximab regardless of the grade of rash, grade of rash was not a useful predictive marker.

Retarded low‐dose doxycycline for EGFR or MEK inhibitor–induced papulopustular rash

Epidermal growth factor receptor inhibitors (EGFRi) and MEK inhibitors (MEKi) are notorious for causing papulopustular rash. Treatment recommendations from studies and expert panels include, amongst others, oral tetracyclines. The efficacy of retarded low-dose doxycycline (rld-doxycycline), however, has not been investigated. The objective was to review the response and development of EGFRi- and MEKi-induced rash under therapy with rld-doxycycline. A retrospective review of all patients treated with rld-doxycyline 40 mg once daily between September 2011 and June 2012 for papulopustular rash. Rash development and severity (according to the Common Terminology Criteria of Adverse Events V4.0) were assessed. Seventeen patients (13 men, 4 women) were treated with rld-doxycycline while receiving EGFRi [monoclonal antibodies (mab) n = 8, tyrosine kinase inhibitors (TKi) n = 7] or MEKi (n = 2). In 47% (n = 8) the rash was reduced by at least one grade, in 29% (n = 5) the rash was stabilized, 24% (n = 4) did not profit from the treatment. All patients treated with an EGFR-TKi or a MEKi profited of the rld-doxycycline. All patients who experienced deterioration were on treatment with an EGFR-mab. Rld-doxycyline can improve EGFR-TKi- and MEKi-induced rash severity. Its effectiveness appears to be inferior to doxycycline 200 mg/day in more severe cases and in EGFR-mab-induced rash, but due to the advantageous side-effect profile, rld-doxycycline should be considered as a possible treatment option for papulopustular rash. Prospective, randomized trials are necessary to confirm these findings.

Evaluation of a novel rash scale and a serum proteomic predictor in a randomized phase II trial of sequential or concurrent cetuximab and pemetrexed in previously treated non-small cell lung cancer

BackgroundCandidate predictive biomarkers for epidermal growth factor receptor inhibitors (EGFRi), skin rash and serum proteomic assays, require further qualification to improve EGFRi therapy in non-small cell lung cancer (NSCLC). In a phase II trial that was closed to accrual because of changes in clinical practice we examined the relationships among candidate biomarkers, quantitative changes in tumor size, progression-free and overall survival.Methods55 patients with progressive NSCLC after platinum therapy were randomized to receive (Arm A) cetuximab, followed by pemetrexed at progression, or (Arm B) concurrent cetuximab and pemetrexed. All received cetuximab monotherapy for the first 14 days. Pre-treatment serum and weekly rash assessments by standard and EGFRi-induced rash (EIR) scales were collected.Results43 patients (20-Arm A, 23-Arm B) completed the 14-day run-in. Median survival was 9.1 months. Arm B had better median overall (Arm B = 10.3 [95% CI 7.5, 16.8]; Arm A = 3.5 [2.8, 11.7] months P = 0.046) and progression-free survival (Arm B = 2.3 [1.6, 3.1]; Arm A = 1.6 [0.9, 1.9] months P = 0.11). The EIR scale distributed ratings among 6 rather than 3 categories but ordinal scale rash severity did not predict outcomes. The serum proteomic classifier and absence of rash after 21 days of cetuximab did.ConclusionsAbsence of rash after 21 days of cetuximab therapy and the serum proteomic classifier, but not ordinal rash severity, were associated with NSCLC outcomes. Although in a small study, these observations were consistent with results from larger retrospective analyses.Trial registrationClinicaltrials.gov Identifier NCT00203931

Bacterial artificial chromosome derived simian varicella virus is pathogenic in vivo

BackgroundVaricella zoster virus (VZV) is a neurotropic alphaherpesvirus that infects humans and results in chickenpox and herpes zoster. A number of VZV genes remain functionally uncharacterized and since VZV is an obligate human pathogen, rigorous evaluation of VZV mutants in vivo remains challenging. Simian varicella virus (SVV) is homologous to VZV and SVV infection of rhesus macaques (RM) closely mimics VZV infection of humans. Recently the SVV genome was cloned as a bacterial artificial chromosome (BAC) and BAC-derived SVV displayed similar replication kinetics as wild-type (WT) SVV in vitro.MethodsRMs were infected with BAC-derived SVV or WT SVV at 4x105 PFU intrabronchially (N=8, 4 per group, sex and age matched). We collected whole blood (PBMC) and bronchoalveolar lavage (BAL) at various days post-infection (dpi) and sensory ganglia during latent infection (>84 dpi) at necropsy and compared disease progression, viral replication, immune response and the establishment of latency.ResultsViral replication kinetics and magnitude in bronchoalveolar lavage cells and whole blood as well as rash severity and duration were similar in RMs infected with SVV BAC or WT SVV. Moreover, SVV-specific B and T cell responses were comparable between BAC and WT-infected animals. Lastly, we measured viral DNA in sensory ganglia from both cohorts of infected RMs during latent infection.ConclusionsSVV BAC is as pathogenic and immunogenic as WT SVV in vivo. Thus, the SVV BAC genetic system combined with the rhesus macaque animal model can further our understanding of viral ORFs important for VZV pathogenesis and the development of second-generation vaccines.

Timing and severity of skin-related adverse events in a phase II trial of sorafenib (BAY43-9006) in patients with advanced thyroid cancer.

e17009 Background: We previously conducted a phase II study of sorafenib (BAY43-9006) in advanced thyroid cancer. Rash and Hand-Foot Skin Reaction (HFSR) were two of the most common adverse events (AEs). Because these skin-related AEs affect quality of life, we further explored their time course and management. Methods: Fifty-five patients were treated on UPCC 03305, a phase II study of sorafenib in patients with advanced thyroid cancer from 2006 to 2011. AEs were recorded using CTCAE v.3.0 and reported here if relation to the drug was deemed “possibly-related” or greater. Cycle length was four weeks. Results: No grade 4 or 5 skin toxicity was observed. Forty-nine patients (89%) experienced rash. Thirty-one patients had a maximum severity of grade 1 (56%), eight had grade 2 (15%), and nine had grade 3 (18%). Fifty patients (91%) had HFSR. Thirteen patients had a maximum severity of grade 1 (24%), 33 had grade 2 (60%), and four had grade 3 (7%). The severity of rash peaked at cycle 1 (19% grade 2,3) and declined by cycle 3 (4% grade 2,3). The severity of HFSR peaked at cycle 2 (39%, grade 2,3) and declined by cycle 6 (10% grade 2,3). The timing and severity of rash and HFSR by cycle are reported in the Table. Following cycle 12 the severity and prevalence of skin AEs reached a steady state. Of the 55 patients, 30 patients (55%) required dose-reduction, and nine of those patients (31%) resumed full dose by the end of study date. Nine patients (16%) were dose-reduced for rash, 17 patients (31%) were dose-reduced for HFSR, and three patients (5%) were dose-reduced for both rash and HFSR. Conclusions: The severity of skin toxicity peaked by cycle 1 for rash and cycle 2 for HFSR. The severity improved dramatically for rash by cycle 3 and for HFSR by cycle 6. Our data support the close supervision of skin-related AEs in the first six cycles of treatment with sorafenib. However, the sustained high prevalence of rash and HFSR requires all patients receive ongoing skin care for the duration of therapy. Clinical trial information: NCT00095693. [Table: see text]

Plasma RANTES, IL-10, and IL-8 levels in non–small-cell lung cancer patients treated with EGFR-TKIs

BackgroundEpidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs), routinely used to treat advanced non-small-cell lung cancer (NSCLC) patients with activated EGFR mutations, are associated with excellent response and improved performance status. Recently, pro-inflammatory cytokines, such as regulated upon activation normal T cell expressed and secreted (RANTES), interleukin (IL)-10 and IL-8 have been proposed as mediators of cancer development. EGFR-TKIs have been found to affect this network of pro-inflammatory cytokines.MethodsEGFR-TKIs (erlotinib, 150 mg/day; and gefitinib, 250 mg/day) were administered once per day. Treatment was continued until disease progressed or the patient developed intolerable symptoms of toxicity, or withdrew his/her consent for study participation. The treatment was a part of standard care. We investigated the correlation between plasma pro-inflammatory cytokines (including plasma RANTES, IL-10, and IL-8) levels and clinical outcomes following EGFR-TKI treatment in lung cancer patients. Pro-inflammatory cytokine levels were evaluated at diagnosis and on treatment day 30 after the first administration of EGFR-TKIs.ResultsOverall, 33 patients were enrolled. Plasma pro-inflammatory cytokine levels were determined for all patients at diagnosis. Plasma samples from 26 patients were obtained on treatment day 30. High level of RANTES at diagnosis was associated with severe general fatigue (P = .026). Low level of RANTES at diagnosis was significantly associated with long-term survival (P = .0032). Percent decrease change of IL-10 was associated with severity of rash (P = .037). The plasma IL-8 level on treatment day 30 (median, 5.48 pg/mL; range, 0.49–26.13 pg/mL) was significantly lower than the level at diagnosis (median 10.45 pg/mL; 3.04–54.86 pg/mL; P = .021).ConclusionsThese results suggest that EGFR-TKIs may suppress systemic inflammation and promote tumor shrinkage. The network of pro-inflammatory cytokines was affected by EGFR-TKI treatment for NSCLC. In addition, the clinical outcomes of EGFR-TKI treatment were influenced by the status of the plasma pro-inflammatory cytokines at diagnosis.

A patient-derived somatic mutation in the epidermal growth factor receptor ligand-binding domain confers increased sensitivity to cetuximab in head and neck cancer

BackgroundCetuximab is an epidermal growth factor receptor (EGFR)-blocking antibody that has been approved for the treatment of patients with head and neck squamous cell carcinoma (HNSCC) and metastatic colorectal cancer, but no predictive biomarkers of activity have been yet identified. Establishment of such biomarkers will help identify a subset of patients that will benefit from cetuximab therapy. MethodsIn this paper, we report on a patient with HNSCC who had a complete tumour regression following treatment with cetuximab given as a single agent after initial surgery and radiation therapy. The EGFR protein expression level, the EGFR gene copy number and the EGFR gene sequence were assessed from both normal and tumour tissues. ResultsBesides protein overexpression and gene amplification in the tumour tissue, sequencing of the EGFR gene from the patient revealed the presence of two somatic mutations, one in the kinase domain (R705G) and the other in the ligand binding domain (P546S). Cells that stably express these EGFR mutants were treated with cetuximab and their sensitivity to the drug was compared to cells expressing the wildtype gene. While P546S mutation sensitised NIH-3T3 cells to cetuximab, R705G had a marginal effect. The double mutant (P546S/R705G) behaved like the P546S mutant, indicating that the mutation in the kinase domain does not contribute to the increased sensitivity to cetuximab. No mutations were found in K-RAS or B-RAF genes and no HPV protein or DNA was detected in the tumour. This is the first report of a somatic mutation in the EGFR ligand binding domain that may contribute to increased sensitivity to cetuximab. ConclusionsOur results support a role for the P546S mutation in cetuximab sensitivity. Other factors including EGFR protein high copy number and protein overexpression may have also contributed to the observed response. The severity of a skin rash developed by this patient and its correlation with the antitumour activity does not exclude the involvement of the immune system (i.e. complement-mediated immune response) as well. The occurrence of the P546S mutation needs to be evaluated in HNSCC, as a well as a prospective evaluation of cetuximab anti-tumour activity in patients with tumours harbouring the mutation.

Analysis of Dermatologic Events in Vemurafenib-Treated Patients With Melanoma

Vemurafenib has been approved for the treatment of patients with advanced BRAF(V600E)-mutant melanoma. This report by the Vemurafenib Dermatology Working Group presents the characteristics of dermatologic adverse events (AEs) that occur in vemurafenib-treated patients, including cutaneous squamous cell carcinoma (cuSCC). Dermatologic AEs were assessed from three ongoing trials of BRAF(V600E) mutation-positive advanced melanoma. Histologic central review and genetic characterization were completed for a subset of cuSCC lesions. A total of 520 patients received vemurafenib. The most commonly reported AEs were dermatologic AEs, occurring in 92%-95% of patients. Rash was the most common AE (64%-75% of patients), and the most common types were rash not otherwise specified, erythema, maculopapular rash, and folliculitis. Rash development did not appear to correlate with tumor response. Photosensitivity occurred in 35%-63% of patients, and palmar-plantar erythrodysesthesia (PPE) occurred in 8%-10% of patients. The severity of rash, photosensitivity, and PPE were mainly grade 1 or 2. In all, 19%-26% of patients developed cuSCC, mostly keratoacanthomas (KAs). The majority of patients with cuSCC continued therapy without dose reduction after resection. Genetic analysis of 29 cuSCC/KA samples demonstrated HRAS mutations in 41%. Dermatologic AEs associated with vemurafenib treatment in patients with melanoma were generally manageable with supportive care measures. Dose interruptions and/or reductions were required in <10% of patients.

Ocular complications and loss of vision due to herpes zoster ophthalmicus in patients with HIV infection and a comparison with HIV-negative patients

The aim of the work is to describe the occurrence of ocular complications and loss of vision due to herpes zoster ophthalmicus (HZO) in HIV-positive patients who received early antiviral therapy for HZO.This is a post hoc analysis of prospectively collected data.Twenty-four HIV-positive patients with HZO were included in this report; male to female ratio was 3.8:1; mean age was 33.5 (±14.9) years. The visual outcome was good, with 14/24 patients having 6/6 vision; severe vision loss (≤6/60) occurred in only 2/24. There was no statistical difference in the visual outcome between the HIV-positive and -negative patients (P = 0.69), although severe vision loss was more likely in HIV-infected patients. The ocular complications of HZO in HIV-infected patients were: reduced corneal sensation (17/24), corneal epithelial lesions (14/24), uveitis (12/24), elevated intraocular pressure (10/24) and extra-ocular muscle palsy (3/24). The severity of rash was similar in the two groups but multidermatomal rash occurred only in HIV-infected patients (4/24). There was no difference in the occurrence of ocular complications of HZO between HIV-positive and HIV-negative patients. HZO associated ocular complications and visual loss is low in HIV-infected patients if treated with HZO antiviral therapy and was comparable with HIV-negative patients. Early institution of HZO antiviral therapy is recommended to reduce ocular complication and vision loss.