Impact of baricitinib in combination with topical steroids on atopic dermatitis symptoms, quality of life and functioning in adult patients with moderate-to-severe atopic dermatitis from the BREEZE-AD7 Phase 3 randomized trial.

BACKGROUND: Baricitinib is an oral, selective, reversible Janus kinase 1/2 inhibitor approved in the European Union and Japan and under investigation in the United States for treatment of atopic dermatitis (AD). OBJECTIVES: To evaluate the impact of baricitinib plus background topical corticosteroids (TCS) on health-related quality of life (HRQoL), how AD symptoms impact work productivity and life functioning, and treatment benefit using patient-reported outcome (PRO) assessments in patients with moderate-to-severe AD previously experiencing inadequate response to TCS. METHODS: Adult patients with AD in BREEZE-AD7, a Phase 3, multicentre, double-blind trial, were randomised 1 : 1 : 1 to daily oral placebo (control) or baricitinib 4- or 2-mg plus TCS. PROs reported Week 1 through Week 16: Dermatology Life Quality Index (DLQI), Work Productivity and Activity Impairment-AD (WPAI-AD); Patient-Reported Outcomes Measurement Information System (PROMIS) Itch and Sleep measures, and Patient Benefit Index (PBI). Data were analysed using logistic regression (categorical) and mixed model repeated measures (continuous). PBI scores were analysed using analysis of variance. RESULTS: A total of 329 patients were randomised. Treatment with baricitinib 4-mg (N = 111) or 2 mg (N = 109) plus TCS led to rapid, statistically significant improvements [vs. TCS plus placebo (N = 109)] in DLQI ≥4-point improvement starting at Week 2 (4-mg plus TCS, P ≤ 0.001; 2-mg plus TCS P ≤ 0.05), change from baseline in WPAI-AD presenteeism at Week 1 (4-mg plus TCS, P ≤ 0.01; 2-mg plus TCS P ≤ 0.05) and PROMIS itch interference at Week 2 (4-mg plus TCS P ≤ 0.01). Improvements were sustained through Week 16 for baricitinib 4-mg. Statistically significant improvements were observed at Week 16 for PBI global score (4-mg plus TCS, P ≤ 0.001; 2-mg plus TCS P ≤ 0.05). CONCLUSIONS: Baricitinib plus TCS vs. placebo plus TCS showed significant improvements in treatment benefit at Week 16 and rapid significant improvements in HRQoL and impact of AD symptoms on work productivity and functioning through 16 weeks.

Efficacy and safety of ixekizumab in a randomized, double-blinded, placebo-controlled phase IIIb study of patients with moderate-to-severe genital psoriasis.

BACKGROUND: Genital psoriasis (GenPs) is a common, debilitating and difficult-to-treat manifestation of plaque psoriasis. However, few controlled, interventional studies of GenPs exist. OBJECTIVES: To determine the efficacy of ixekizumab vs. placebo in patients with moderate-to-severe GenPs with ≥ 1% involved body surface area (BSA). METHODS: Patients with moderate-to-severe GenPs, defined as a baseline static Physician's Global Assessment of Genitalia (sPGA-G) score of ≥ 3, with BSA ≥ 1% were randomized 1 : 1 to receive placebo (n = 74) or the recommended dosing of ixekizumab (n = 75). Major outcomes included the percentage of patients achieving 0 or 1 scores on the sPGA-G (primary end point), overall sPGA, GenPs Sexual Frequency Questionnaire (GenPs-SFQ) item 2, and ≥ 3-point improvement from baseline on the GenPs itch numerical rating scale. RESULTS: At week 12, ixekizumab was superior to placebo for sPGA-G 0/1 (73% vs. 8%, P < 0·001), overall sPGA 0/1 (73% vs. 3%, P < 0·001), GenPs-SFQ item 2 score of 0 or 1 (78% vs. 21%, P < 0·001) and genital itch (60% vs. 8%, P < 0·001). No candidiasis was reported, no deaths occurred and one (1%) serious adverse event was reported in a patient receiving placebo. CONCLUSIONS: Ixekizumab was superior to placebo for the treatment of moderate-to-severe GenPs with BSA ≥ 1%. The safety profile of ixekizumab was consistent with previous studies in moderate-to-severe plaque psoriasis.

A new look at an old option in the treatment of early-stage prostate cancer: hormone therapy as an alternative to watchful waiting.

Watchful waiting is an attractive option in the management of early-stage, low-grade prostate cancer because of the high financial costs and complication risks associated with surgery and radiotherapy. Despite the drawbacks of current local therapy, neither treatment can demonstrate a discernible survival benefit over observation alone. Even the slowest progressing disease, however, can potentially develop into a deadly medical problem. As a result, physicians and patients frequently have difficulty accepting untreated cancer. Therefore, we propose that another option be considered in cases of prostate cancer that would otherwise qualify for observation alone: the use of two oral hormonal agents, flutamide and finasteride, to achieve complete androgen blockade. Some evidence exists which suggests that such therapy may improve symptom-free survival, and perhaps overall survival as well. This 'aggressive' form of 'conservative' therapy may satisfy patient concerns that are not adequately addressed by current forms of therapy.

The potential for normal tissue dose reduction with neoadjuvant hormonal therapy in conformal treatment planning for stage C prostate cancer.

PURPOSE: Preirradiation hormonal cytoreduction of prostate cancer has been proven to reduce exposure of normal structures by decreasing the size of the target volume. Dose-volume histogram (DVH) analysis, however, does not always appear to demonstrate a strong positive benefit with the use of neoadjuvant hormone therapy. This study analyzes various other factors influencing dose to normal organs, which may determine the success or failure of neoadjuvant hormonal therapy in achieving its goals. METHODS AND MATERIALS: Patients with bulky clinical Stage C adenocarcinoma of the prostate were given 3 months of hormone treatment consisting of oral Flutamide and monthly Zoladex injections prior to irradiation. Computerized tomography (CT) scans of the pelvis were obtained both prior to and following hormonal treatment. Treatment plans were generated by three-dimensional (3D) conformal treatment planning. The change in the volume of the prostate was assessed along with the percentage of prescribed dose delivered to the rectum and bladder. Various factors such as prostate size, bladder/rectum size, and organ shape were studied. Both dose-volume histograms (DVH) and dose-surface area histograms (DSH) were used for analysis. RESULTS: Six of seven patients had reduction in the size of their prostates. The mean volumes of the prostate before and after hormonal manipulation were 129.1 +/- 32.9 standard deviation (SD) cm3 and 73.0 +/- 29.5 SD cm3, respectively (p = 0.0059). The volume of rectum receiving 80% of the prescribed dose was reduced in five of seven patients from a mean of 83.2 to 59.9 cm3 (p = 0.045). The volume of bladder receiving 80% of the prescribed dose was also reduced in five out of seven patients from a mean of 74.5 to 40.2 cm3 (p = 0.098). Correlation between the size of the prostate and volume of rectum and bladder treated was not always consistent: greater reduction in prostate size did not necessarily result in large decreases in dose to bladder or rectum. The total size of the bladder and rectum were found to be important factors in normal tissue radiation exposure; the benefits of hormone therapy may be lost if the bladder and rectum are allowed to decrease in size. Also, the bladder may be prone to sagging into the pelvis of some patients following hormone therapy, resulting in a less optimal therapeutic ratio. CONCLUSION: Reduction in prostate size by neoadjuvant hormonal manipulation does decrease the amount of normal tissue irradiated in most patients. However, the correlation between the reduction in prostate size and amount of rectum or bladder treated is not linear if other variables are not controlled. Factors such as the shape of the organs, as well as the distensible nature of the bladder and rectum, play major roles in dose to normal tissues. These facts may mask the benefits of cytoreduction and could be obstacles in realizing consistent benefits from preirradiation hormonal treatment in the clinical setting if they are ignored.

Analysis of weekly complete blood counts in patients receiving standard fractionated partial body radiation therapy.

PURPOSE: Hematopoiesis is among the most sensitive systems in the body to radiation. Routine complete blood counts (CBCs) are common in clinical radiotherapy practice. Only a few studies have attempted to characterize the behavior of peripheral blood levels during partial body radiation therapy with field sizes smaller than those used in hemibody or total nodal irradiation. Such information is needed to identify which patients are at risk for cytopenia and require close monitoring. METHODS AND MATERIALS: In 1993, 412 new patients were seen at Michael Reese Hospital for radiotherapy. A total of 972 weekly CBCs were identified for 155 patients receiving a minimum of 5 weeks of treatment for breast, prostate, lung, gynecological, or head and neck malignancies. Linear regression models were fitted to the weekly CBC values for those patients who had pretreatment CBC values recorded. Factors affecting starting levels, rates of decline, and nadirs during treatment were determined for leukocytes, platelets, and hemoglobin. RESULTS: Leukocytes declined most dramatically during the first week of treatment (16% from pretreatment to Week 1 levels) and then at a rate of 3.3% per week from Week 1 to Week 7 (p < 0.001). Total mean leukocyte decrease over 7 weeks of therapy was 30%. Platelets declined 9% on average during the first week of therapy and then at a mean rate of 1.4% per week (p < 0.02). A statistically significant decrease in hemoglobin levels could not be detected. No difference in the rate of decrease could be found for different disease sites, age groups, or amount of marrow irradiated. The effects of chemotherapy were variable, depending on blood element and whether therapy was sequential or concomitant. The odds of a nadir < 2000 counts/mm3 for white blood count (WBC), < 50,000 counts/mm3 for platelets, and < 8.0 g/dl for hemoglobin were all well below 5%. A strong correlation existed between starting CBC values and nadirs; patients with lower Week 1 CBC levels were most likely to have the lowest nadirs. CONCLUSIONS: Low CBC levels during radiation therapy are likely to be the result of other medical problems that cancer patients face. Regional irradiation with small field sizes (< 40% of total body marrow) typically used in clinical radiotherapy is unlikely to be the cause of marrow depression significant enough to warrant medical intervention. Blood levels taken during the first week of treatment (Week 1) can be used to determine risks of developing critical nadirs. Localized breast and prostate cancer patients are unlikely to require routine CBCs if initial levels are normal. Routine CBC levels on all radiation oncology patients without other reasons for hematopoietic depression requires reevaluation, as millions of dollars are spent on unnecessary testing. If weekly CBC blood levels are avoided in localized breast and prostate cancer patients, this alone could potentially result in a savings of as much as $40 million a year nationally.

Autoradiography-based, three-dimensional calculation of dose rate for murine, human-tumor xenografts.

A Fast Fourier Transform method for calculating the three-dimensional dose rate distribution for murine, human-tumor xenografts is outlined. The required input includes evenly-spaced activity slices which span the tumor. Numerical values in these slices are determined by quantitative 125I autoradiography. For the absorbed dose-rate calculation, we assume the activity from both 131I- and 90Y-labeled radiopharmaceuticals would be distributed as is measured with the 125I label. Two example cases are presented: an ovarian-carcinoma xenograft with an IgG 2ak monoclonal antibody and a neuroblastoma xenograft with meta-iodobenzylguanidine (MIBG). Considering all the volume elements in a tumor, we show, by comparison of histograms and also relative standard deviations, that the measured 125I activity and the calculated 131I dose-rate distributions, are similarly non-uniform and that they are more non-uniform than the calculated 90Y dose-rate distribution. However, the maximum-to-minimum ratio, another measure of non-uniformity, decreases by roughly an order of magnitude from one distribution to the next in the order given above.

Quantitative autoradiographic evaluation of the influence of protein dose on monoclonal antibody distribution in human ovarian adenocarcinoma xenografts.

We studied the effect of monoclonal antibody protein dose on the uniformity of radioiodinated antibody distribution within tumor masses using quantitative autoradiography. Groups (n = 11-13/group) of athymic nude mice with subcutaneous HTB77 human ovarian carcinoma xenografts were injected intraperitoneally with an 125I-labeled anticarcinoma-associated antigen murine monoclonal antibody, 5G6.4 using a high or a low protein dose (500 micrograms or 5 micrograms). At 6 days post-injection the macroscopic and microscopic intratumoral biodistribution of radiolabeled antibody was determined. The degree of heterogeneity of the labeled antibody distribution within each tumor was quantified and expressed as the coefficient of variation (CV) of the activity levels in serial histological sections. Tumors from mice given the 500-micrograms protein doses had substantially lower CV values, 0.327 +/- 0.027, than did tumors from animals given 5-micrograms protein doses, 0.458 +/- 0.041, (P = 0.0078), indicating that the higher protein dose resulted in more homogeneous distribution of radioactivity in tumors than did the lower dose. While the percentage of the injected dose reaching the tumor was comparable between groups, injecting the higher dose of protein resulted in significantly lower tumor to non-tumor uptake ratios than those obtained for the lower protein dose. These data indicate, in this system, that to achieve more uniform intratumoral antibody (and radiation for radioimmunotherapy) delivery, a relatively high protein dose must be administered. However, to obtain this increased uniformity, a substantial drop in tumor/background uptake ratios was seen. Quantitative autoradiographic evaluation of human tumor xenografts is a useful method to assess the intratumoral distribution of antibodies.