Analysis of the association between prospectively collected immune-related adverse events and survival in patients with solid tumor treated with immune-checkpoint blockers, taking into account immortal-time bias.

BACKGROUND: Numerous retrospective studies and reviews have reported a positive association between immune-related adverse events (irAEs) and survival in non-small cell lung cancer (NSCLC) and melanoma patients treated with immune checkpoint blockers (ICBs). However, some results are controversial and the studies, whose results converge, should be interpreted cautiously because most of them do not deal appropriately with the immortal-time bias. Here, we report an observational real-life study of the association between prospectively collected irAEs and survival of patients treated with ICBs while dealing with the immortal-time bias. METHODS: Data from patients treated at Gustave Roussy from June 2014 to October 2017 with anti-PD-(L)1 antibodies for a melanoma or NSCLC have been prospectively collected in the REISAMIC database, a pharmacovigilance registry dedicated to irAEs. Adverse events of grade 2 and higher were collected prospectively. To study the association between the occurrence of irAEs and survival, we used both a landmark analysis and a Cox regression model with time-dependent covariate. RESULTS: 577 patients were treated with anti-PD-(L)1 antibodies for melanoma (60.3 %) or NSCLC (39.7 %). The occurrence of an irAE was significantly associated with improved overall survival (OS): HR 0.56, 95 % CI [0.41; 0.75], p = 0.0001 and progression-free survival (PFS): HR 0.63, 95 % CI [0.47; 0.83], p = 0.001 using a Cox regression model with time-dependent covariate. In a 12-week landmark analysis, median OS was 21.2 months (95 % CI, 12.2 to 35.7) and 16.4 months (95 % CI, 12.4 to 21.3) p = 0.26 and median PFS was 14.3 months (95 % CI, 9.5 to 24.6) and 13.4 months (95 % CI, 10.2 to 18.3) p = 0.66, for patients with and without irAEs, respectively. CONCLUSIONS: In our real-life study of patients with melanoma and NSCLC treated with anti-PD-(L)1 antibodies, we confirm that irAEs are associated with improved survival using a time-varying Cox regression model. Analysis with a landmark method showed no difference in OS or PFS between patients who experienced irAE during the first 12 weeks of treatment and those who did not. Retrospective analysis and reviews including studies that do not deal with the immortal-time bias and studies insufficiently powered for a landmark analysis should be interpreted with caution.

Early hepatocellular carcinoma detection using magnetic resonance imaging is cost-effective in high-risk patients with cirrhosis.

BACKGROUND & AIMS: Reinforced hepatocellular carcinoma (HCC) surveillance using magnetic resonance imaging (MRI) could increase early tumour detection but faces cost-effectiveness issues. In this study, we aimed to evaluate the cost-effectiveness of MRI for the detection of very early HCC (Barcelona Clinic Liver Cancer [BCLC] 0) in patients with an annual HCC risk >3%. METHODS: French patients with compensated cirrhosis included in 4 multicentre prospective cohorts were considered. A scoring system was constructed to identify patients with an annual risk >3%. Using a Markov model, the economic evaluation estimated the costs and life years (LYs) gained with MRI vs. ultrasound (US) monitoring over a 20-year period. The incremental cost-effectiveness ratio (ICER) was calculated by dividing the incremental costs by the incremental LYs. RESULTS: Among 2,513 patients with non-viral causes of cirrhosis (n = 840) and/or cured HCV (n = 1,489)/controlled HBV infection (n = 184), 206 cases of HCC were detected after a 37-month follow-up. When applied to training (n = 1,658) and validation (n = 855) sets, the construction of a scoring system identified 33.4% and 37.5% of patients with an annual HCC risk >3% (3-year C-Indexes 75 and 76, respectively). In patients with a 3% annual risk, the incremental LY gained with MRI was 0.4 for an additional cost of €6,134, resulting in an ICER of €15,447 per LY. Compared to US monitoring, MRI detected 5x more BCLC 0 HCC. The deterministic sensitivity analysis confirmed the impact of HCC incidence. At a willingness to pay of €50,000/LY, MRI screening had a 100% probability of being cost-effective. CONCLUSIONS: In the era of HCV eradication/HBV control, patients with annual HCC risk >3% represent one-third of French patients with cirrhosis. MRI is cost-effective in this population and could favour early HCC detection. LAY SUMMARY: The early identification of hepatocellular carcinoma in patients with cirrhosis is important to improve patient outcomes. Magnetic resonance imaging could increase early tumour detection but is more expensive and less accessible than ultrasound (the standard modality for surveillance). Herein, using a simple score, we identified a subgroup of patients with cirrhosis (accounting for >one-third), who were at increased risk of hepatocellular carcinoma and for whom the increased expense of magnetic resonance imaging would be justified by the potential improvement in outcomes.

Intravitreal bevacizumab for neovascular glaucoma in uveal melanoma treated by proton beam therapy.

BACKGROUND: To evaluate the efficacy of bevacizumab on reduction of the enucleation rate and control of intraocular pressure (IOP) in neovascular glaucoma (NVG)-complicating proton beam therapy for UM and to identify the determinants of the efficacy of bevacizumab. METHODS: Retrospective comparative study of patients with rubeosis following proton therapy for uveal melanoma. Patients were divided into two groups: a bevacizumab group and a control group which comprised two subgroups: panretinal photocoagulation (PRP)/cryotherapy and observation subgroups. Bevacizumab was administered by three intravitreal injections at 1-month intervals. A second series of injections was administered when necessary. Data concerning IOP and the secondary enucleation rate were collected and compared between the two groups. Univariate and multivariate analyses were performed to determine predictive factors of response to bevacizumab. RESULTS: A total of 169 patients who developed rubeosis following proton therapy between 2006 and 2016 were included: 44 patients in the bevacizumab group and 125 in the control group (38 in the PRP/cryotherapy subgroup and 87 in the observation subgroup). The two groups presented the same baseline characteristics apart from hypertension, retro-equatorial site, and proximity of the optic disk, which were more frequent in the control group, while initial retinal detachment and larger tumor volume were more frequent in the bevacizumab group. After a mean follow-up of 31 months, IOP was less than 21 mmHg in 54.54% of patients after IVB versus 72.7% before treatment (p = 0.06). Statistical analysis did not reveal any statistically significant reduction of the enucleation rate in the bevacizumab group compared to the observational group, whereas the PRP/cryotherapy group showed better eye retention rate (p = 0.15). No enucleation was performed when IOP was < 21 mmHg before IVB. Multivariate analysis identified initial IOP < 21 mmHg and UM situated away from the macula as predictive factors of good response to bevacizumab. CONCLUSION: Despite the improvement of IOP level, intravitreal bevacizumab (IVB) did not reduce the overall enucleation rate in NVG following proton beam therapy. Nevertheless, this treatment was effective in the early phases of NVG or as preventive treatment. PRP remains a valid treatment for NVG.