Safety of nivolumab monotherapy in five cancer types: pooled analysis of post-marketing surveillance in Japan.

BACKGROUND: Nivolumab has been approved for treating ≥ 10 cancer types. However, there is limited information on the incidence of rare, but potentially serious, treatment-related adverse events (TRAEs), as well as notable TRAEs in patients with certain medical disorders or older patients in Japan. METHODS: We performed pooled analyses of data from published post-marketing surveillance in Japan of nivolumab monotherapy for patients with malignant melanoma, non-small cell lung cancer, renal cell carcinoma, head and neck cancer, and gastric cancer to determine the frequencies of 20 categories of TRAEs of special interest overall and in patient groups with higher perceived safety risks (history of autoimmune disease, interstitial lung disease, tuberculosis, or hepatitis B/C; patients vaccinated during nivolumab treatment; and older patients [≥ 75 years]). RESULTS: The overall population comprised 7421 patients treated with nivolumab. TRAEs were reported in 49.1% of patients, with grade ≥ 3 TRAEs in 16.7%. Endocrine disorders (14.4%), hepatobiliary disorders (10.9%), and interstitial lung disease (7.0%) were the three most common categories (any grade). The incidences of rare TRAEs with high risk of becoming serious, which occurred in < 1% of patients, were consistent with those in previous reports. The frequencies of TRAEs were not markedly increased in the specified patient groups relative to the overall population. CONCLUSION: To our knowledge, this is the largest study examining the safety of nivolumab-treated patients in real-world clinical practice including rare but potentially serious TRAEs. We found no new signals in the safety of nivolumab among the patient groups relative to the overall population, and no additional safety measures are required in these groups. Trial registration UMIN000048892 (overall analysis), JapicCTI-163272 (melanoma), Japic-163271 (non-small cell lung cancer), JapicCTI-184071 (head and neck cancer), JapicCTI-184070 (gastric cancer), and JapicCTI-184069 (renal cell cancer).

Real-world safety and effectiveness of anamorelin for cancer cachexia: Interim analysis of post-marketing surveillance in Japan.

BACKGROUND: Anamorelin was approved in Japan in 2021 to treat cancer cachexia associated with non-small cell lung, gastric, pancreatic, or colorectal cancers. Post-marketing surveillance is being conducted to evaluate the real-world safety and effectiveness of anamorelin. METHODS: This prospective, observational surveillance registered all patients who started treatment with anamorelin after April 21, 2021. Hyperglycemia, hepatic impairment, conduction disorders, and their associated adverse events related to treatment were defined as main safety specifications. Body weight (BW) and appetite were assessed as effectiveness specifications. RESULTS: This analysis was based on data as of January 21, 2023. The safety and effectiveness analysis sets included 6016 and 4511 patients, respectively. Treatment-related adverse events in ≥1% of patients were hyperglycemia (3.9%) and nausea (2.6%). The incidences of hyperglycemia, hepatic impairment, conduction disorders, and their associated adverse events related to treatment were 4.8%, 1.2%, and 1.1%, respectively. The mean changes (standard error [SE]) in BW from baseline to weeks 3, 12, 24, and 52 were 0.64 (0.05) kg, 1.19 (0.12) kg, 1.40 (0.21) kg, and 1.42 (0.39) kg, respectively. The mean changes (SE) in Functional Assessment of Anorexia/Cachexia Treatment 5-item Anorexia Symptom Scale total scores from baseline to weeks 3, 12, 24, and 52 were 3.2 (0.09), 4.8 (0.18), 5.2 (0.30), and 5.3 (0.47), respectively, exceeding the clinically meaningful improvement score (2.0 points). CONCLUSION: The overall safety of anamorelin raised no new safety concerns, although continued caution may be required for hyperglycemia and nausea. Improvements in BW and appetite were also observed in real-world clinical settings.

Homogeneity score test of AC1 statistics and estimation of common AC1 in multiple or stratified inter-rater agreement studies.

BACKGROUND: Cohen's κ coefficient is often used as an index to measure the agreement of inter-rater determinations. However, κ varies greatly depending on the marginal distribution of the target population and overestimates the probability of agreement occurring by chance. To overcome these limitations, an alternative and more stable agreement coefficient was proposed, referred to as Gwet's AC1. When it is desired to combine results from multiple agreement studies, such as in a meta-analysis, or to perform stratified analysis with subject covariates that affect agreement, it is of interest to compare several agreement coefficients and present a common agreement index. A homogeneity test of κ was developed; however, there are no reports on homogeneity tests for AC1 or on an estimator of common AC1. In this article, a homogeneity score test for AC1 is therefore derived, in the case of two raters with binary outcomes from K independent strata and its performance is investigated. An estimation of the common AC1 between strata and its confidence intervals is also discussed. METHODS: Two homogeneity tests are provided: a score test and a goodness-of-fit test. In this study, the confidence intervals are derived by asymptotic, Fisher's Z transformation and profile variance methods. Monte Carlo simulation studies were conducted to examine the validity of the proposed methods. An example using clinical data is also provided. RESULTS: Type I error rates of the proposed score test were close to the nominal level when conducting simulations with small and moderate sample sizes. The confidence intervals based on Fisher's Z transformation and the profile variance method provided coverage levels close to nominal over a wide range of parameter combination. CONCLUSIONS: The method proposed in this study is considered to be useful for summarizing evaluations of consistency performed in multiple or stratified inter-rater agreement studies, for meta-analysis of reports from multiple groups and for stratified analysis.

Evaluation of rectal bleeding factors associated with prostate brachytherapy.

PURPOSE: To analyze rectal bleeding prognostic factors associated with prostate brachytherapy (PB) or in combination with external-beam radiation therapy (EBRT) and to examine dosimetric indications associated with rectal bleeding. MATERIALS AND METHODS: The study included 296 patients followed up for >36 months (median, 48 months). PB was performed alone in 252 patients and in combination with EBRT in 44 patients. PB combined with EBRT is indicated for patients with a Gleason score >6. The prescribed dose was 144 Gy for monotherapy and 110 Gy for PB + EBRT (44-46 Gy). RESULTS: Although 9.1% who received monotherapy had 2.3% grade 2 rectal bleeding, 36.3% who received combined therapy had 15.9% grade 2 rectal bleeding. Combined therapy was associated with higher incidence of rectal bleeding (P = 0.0049) and higher percentage of grade 2 bleeding (P = 0.0005). Multivariate analysis revealed that R-150 was the only significant factor for rectal bleeding, and modified Radiation Therapy Oncology Group (RTOG) grade in monotherapy and biologically equivalent dose (BED) were significant for combined therapy. Moreover, grade 2 rectal bleeding increased significantly at D90 > 130 Gy. CONCLUSION: Although R-150 was the significant prognostic factor for rectal bleeding and modified RTOG rectal toxicity grade, BED was the significant prognostic factor for modified RTOG rectal toxicity grade.

[Changes of edema associated with I-125 prostate brachytherapy].

We have been performing TRUS-guided transperineal prostate brachytherapy with I-125 for prostate-confined adenocarcinoma since October 2003. We examined prostate volume using CT scanning on Day 1, Day 15, and Day 30 in the initial 15 patients, and investigated time-dependent changes of edema associated with I-125 prostate brachytherapy. Prostate volume had increased to 173% of the average on the first day after implantation. Improvements in the swelling of the prostate showed decreases in 30% in the first 2 weeks (Days 1-15) and 12% in the second 2 weeks (Days 15-30). V100 and D 90% showed statistically significant increases of 5.5% and 8.4% in the first 2 weeks after implantation and 2.3% and 5.2% in the second 2 weeks (Days 15-30). We considered one month a suitable time at which to calculate post-planning because V100 and D 90% changed little statistically.

Long-term, irradiation-induced effects on thermoregulation in the skin after thermal stimulation.

PURPOSE: The morphological effect of radiation on the skin has been adequately analyzed, but the functional effect has received little attention. The purpose of this study was to examine the long-term effects of radiation on the skin from the viewpoint of function. MATERIALS AND METHODS: Physiological changes in the irradiated skin of patients who had undergone breast-conserving therapy for the treatment of breast cancer were examined throughout the follow-up period. Thermal stimulation was applied to both breasts, and changes in skin temperature and sweating reactivity of irradiated and non-irradiated skin were measured. RESULTS: From three weeks to the end of radiotherapy, the resting skin temperature of the irradiated region was significantly elevated, while the rate of sweating was lower. More than two years after radiotherapy, the elevated resting skin temperature of the irradiated region had returned to within the range observed for non-irradiated skin, although an abnormally high increase in skin temperature after thermal stimulation continued to be observed for more than two years after radiotherapy. At the same time, sweating after thermal stimulation continued to be suppressed. CONCLUSION: Present observations suggest that functional effects, such as the skin temperature and sweating ability of irradiated skin, persist longer than readily visible morphological changes.