Summary Background Sunitinib and sorafenib are oral vascular endothelial growth factor receptor (VEGFR) tyrosine-kinase inhibitors used in various cancers. Bleeding has been described with these ...agents, although the overall risk remains unclear. We did a systematic review and meta-analysis to calculate the incidence and relative risk associated with use of sunitinib and sorafenib. Methods We searched PubMed (from January, 1966, to April, 2009) and meeting proceedings of the American Society of Clinical Oncology and the European Society of Medical Oncology (2004–09) for relevant clinical trials. Eligible studies included phase 2 and 3 trials and expanded-access programmes. Statistical analyses were done to calculate summary incidences, relative risks, and 95% CI, using random-effects or fixed-effects models based on the heterogeneity of included studies. Findings 23 trials were selected for the meta-analysis, yielding a total of 6779 patients. The incidence of bleeding events (all grades) was 16·7% (95% CI 12·7–21·5), and that of high-grade events was 2·4% (1·6–3·9). The relative risk of all-grade bleeding events associated with sunitinib and sorafenib (for randomised controlled trials only) was 2·0 (1·14–3·49; p=0·015). Our analysis was also stratified by underlying malignant disease (renal-cell carcinoma vs non-renal-cell carcinoma) and agent used, but no differences were recorded. Interpretation Treatment with the VEGFR tyrosine-kinase inhibitors sunitinib and sorafenib is associated with a significant increase in risk of bleeding. Funding None.
Abstract Given the lack of randomized evidence comparing trimodal therapy (TMT) to radical cystectomy (RC) for muscle-invasive urothelial carcinoma of the bladder (UCB), we performed an observational ...cohort study to examine the comparative effectiveness of these two definitive treatments. Within the National Cancer Data Base (2004–2011),we identified 1257 (9.8%) and 11 586 (90.2%) patients who received TMT and RC, respectively. Inverse probability of treatment weighting (IPTW)–adjusted Kaplan-Meier analysis showed that median overall survival (OS) was similar between the TMT (40 mo, 95% confidence interval CI 34–46) and RC groups (43 mo 95% CI 41–45; p = 0.3). In IPTW-adjusted Cox regression analysis with a time-varying covariate, TMT was associated with a significant adverse impact on long-term OS (hazard ratio 1.37, 95% CI 1.16–1.59; p < 0.001). Interaction terms indicated that the adverse treatment effect of TMT versus RC decreased with age ( p = 0.004), while there was no significant interaction with gender ( p = 0.6), Charlson comorbidity index ( p = 0.09) or cT stage ( p = 0.8). In conclusion, we found that TMT was generally associated with worse long-term OS compared to RC for muscle-invasive UCB. However, the survival benefit of RC should be weighed against the risks of surgery, especially in older patients. These results are preliminary and emphasize the need for a randomized controlled trial to compare TMT versus RC. Patient summary We examined the comparative effectiveness of trimodal therapy versus radical cystectomy for muscle-invasive urothelial carcinoma of the bladder. We found that trimodal therapy was generally associated with worse long-term overall survival, although there may be no difference with radical cystectomy in older individuals.
Immune checkpoint inhibitors (ICIs) have yielded remarkable responses but often lead to immune-related adverse events (irAEs). Although germline causes for irAEs have been hypothesized, no individual ...variant associated with developing irAEs has been identified. We carried out a genome-wide association study of 1,751 patients on ICIs across 12 cancer types. We investigated two irAE phenotypes: (1) high-grade (3-5) and (2) all-grade events. We identified 3 genome-wide significant associations (P < 5 × 10
) in the discovery cohort associated with all-grade irAEs: rs16906115 near IL7 (combined P = 3.6 × 10
; hazard ratio (HR) = 2.1); rs75824728 near IL22RA1 (combined P = 3.5 × 10
; HR = 1.8); and rs113861051 on 4p15 (combined P = 1.2 × 10
, HR = 2.0); rs16906115 was replicated in 3 independent studies. The association near IL7 colocalized with the gain of a new cryptic exon for IL7, a critical regulator of lymphocyte homeostasis. Patients carrying the IL7 germline variant exhibited significantly increased lymphocyte stability after ICI initiation, which was itself predictive of downstream irAEs and improved survival.
Several reports suggest that cisplatin is associated with an increased risk of thromboembolism. However, because the excess risk of venous thromboembolic events (VTEs) with cisplatin-based ...chemotherapy has not been well described, we conducted a systemic review and meta-analysis of randomized controlled trials evaluating the incidence and risk of VTEs associated with cisplatin-based chemotherapy.
PubMed was searched for articles published from January 1, 1990, to December 31, 2010. Eligible studies included prospective randomized phase II and III trials evaluating cisplatin-based versus non-cisplatin-based chemotherapy in patients with solid tumors. Data on all-grade VTEs were extracted. Study quality was calculated using Jadad scores. Incidence rates, relative risks (RRs), and 95% CIs were calculated using a random effects model.
A total of 8,216 patients with various advanced solid tumors from 38 randomized controlled trials were included. The incidence of VTEs was 1.92% (95% CI, 1.07 to 2.76) in patients treated with cisplatin-based chemotherapy and 0.79% (95% CI, 0.45 to 1.13) in patients treated with non-cisplatin-based regimens. Patients receiving cisplatin-based chemotherapy had a significantly increased risk of VTEs (RR, 1.67; 95% CI, 1.25 to 2.23; P = .01). Exploratory subgroup analysis revealed the highest RR of VTEs in patients receiving a weekly equivalent cisplatin dose > 30 mg/m(2) (2.71; 95% CI, 1.17 to 6.30; P = .02) and in trials reported during 2000 to 2010 (1.72; 95% CI, 1.27 to 2.34; P = .01).
Cisplatin is associated with a significant increase in the risk of VTEs in patients with advanced solid tumors when compared with non-cisplatin-based chemotherapy.
Given the lack of randomized trials comparing robot-assisted radical prostatectomy (RARP) and open radical prostatectomy (ORP), we sought to re-examine the outcomes of these techniques using a cohort ...of patients treated in the postdissemination era.
Overall, data from 5,915 patients with prostate cancer treated with RARP or ORP within the SEER-Medicare linked database diagnosed between October 2008 and December 2009 were abstracted. Postoperative complications, blood transfusions, prolonged length of stay (pLOS), readmission, additional cancer therapies, and costs of care within the first year after surgery were compared between the two surgical approaches. To decrease the effect of unmeasured confounders, instrumental variable analysis was performed. Multivariable logistic regression analyses were then performed.
Overall, 2,439 patients (41.2%) and 3,476 patients (58.8%) underwent ORP and RARP, respectively. In multivariable analyses, patients undergoing RARP had similar odds of overall complications, readmission, and additional cancer therapies compared with patients undergoing ORP. However, RARP was associated with a higher probability of experiencing 30- and 90-day genitourinary and miscellaneous medical complications (all P ≤ .02). Additionally, RARP led to a lower risk of experiencing blood transfusion and of having a pLOS (all P < .001). Finally, first-year reimbursements were greater for patients undergoing RARP compared with ORP (P < .001).
RARP and ORP have comparable rates of complications and additional cancer therapies, even in the postdissemination era. Although RARP was associated with lower risk of blood transfusions and a slightly shorter length of stay, these benefits do not translate to a decrease in expenditures.
Abstract Background Neutrophil-to-lymphocyte ratio (NLR), if elevated, is associated with worse outcomes in several malignancies. Objective Investigation of NLR at baseline and during therapy for ...metastatic renal cell carcinoma. Design, setting, and participants Retrospective analysis of 1199 patients from the International Metastatic Renal Cell Carcinoma Database Consortium (IMDC cohort) and 4350 patients from 12 prospective randomized trials (validation cohort). Intervention Targeted therapies for metastatic renal cell carcinoma. Outcome measurements and statistical analysis NLR was examined at baseline and 6 (± 2) wk later. A landmark analysis at 8 wk was conducted to explore the prognostic value of relative NLR change on overall survival (OS), progression-free survival (PFS), and objective response rate using Cox or logistic regression models, adjusted for variables in IMDC score and NLR values at baseline. Results and limitations Higher NLR at baseline was associated with shorter OS and PFS (Hazard Ratios HR per 1 unit increase in log-transformed NLR = 1.69 95% confidence interval {CI} = 1.46–1.95 and 1.30 95% CI = 1.15–1.48, respectively). Compared with no change (decrease < 25% to increase < 25%, reference), increase NLR at Week 6 by 25–50% and > 75% was associated with poor OS (HR = 1.55 95% CI = 1.10–2.18 and 2.31 95% CI = 1.64–3.25, respectively), poor PFS (HR = 1.46 95% CI = 1.04–2.03, 1.76 95% CI = 1.23–2.52, respectively), and reduced objective response rate (odds ratios = 0.77 95% CI = 0.37–1.63 and 0.24 95% CI = 0.08–0.72, respectively). By contrast, a decrease of 25–50% was associated with improved outcomes. Findings were confirmed in the validation cohort. The study is limited by its retrospective design. Conclusions Compared with no change, early decline of NLR is associated with favorable outcomes, whereas an increase is associated with worse outcomes. Patient summary We found that the proportion of immune cells in the blood is of prognostic value, namely that a decrease of the proportion of neutrophils-to-lymphocytes is associated with more favorable outcomes while an increase had the opposite effect.
The phase 3 JAVELIN Renal 101 trial of avelumab + axitinib vs sunitinib in patients with treatment‐naive advanced renal cell carcinoma (RCC) demonstrated significantly improved progression‐free ...survival (PFS) and higher objective response rate (ORR) with the combination vs sunitinib. Japanese patients enrolled in the study (N = 67) were randomized to receive avelumab + axitinib (N = 33) or sunitinib (N = 34); 67% vs 59% had PD‐L1+ tumors (≥1% of immune cells) and 6%/64%/27% vs 6%/82%/12% had International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) favorable/intermediate/poor risk status. In patients who received avelumab + axitinib vs sunitinib, median PFS (95% confidence interval CI) was not estimable (8.1 months, not estimable) vs 11.2 months (1.6 months, not estimable) (hazard ratio HR, 0.49; 95% CI, 0.152, 1.563) in patients with PD‐L1+ tumors and 16.6 months (8.1 months, not estimable) vs 11.2 months (4.2 months, not estimable) (HR, 0.66; 95% CI, 0.296, 1.464) in patients irrespective of PD‐L1 expression. Median overall survival (OS) has not been reached in either arm in patients with PD‐L1+ tumors and irrespective of PD‐L1 expression. ORR (95% CI) was 60.6% (42.1%, 77.1%) vs 17.6% (6.8%, 34.5%) in patients irrespective of PD‐L1 expression. Common treatment‐emergent adverse events (all grade; grade ≥3) in each arm were hand‐foot syndrome (64%; 9% vs 71%; 9%), hypertension (55%; 30% vs 44%; 18%), hypothyroidism (55%; 0% vs 24%; 0%), dysgeusia (21%; 0% vs 56%; 0%) and platelet count decreased (3%; 0% vs 65%; 32%). Avelumab + axitinib was efficacious and tolerable in treatment‐naive Japanese patients with advanced RCC, which is consistent with results in the overall population.
The phase 3 JAVELIN Renal 101 trial of avelumab + axitinib vs sunitinib in patients with treatment‐naive advanced renal cell carcinoma (RCC) demonstrated significantly improved progression‐free survival (PFS) and higher objective response rate (ORR) with the combination vs sunitinib. In Japanese patients who received avelumab + axitinib vs sunitinib, median PFS (95% CI) was not estimable (8.1 months, not estimable) vs 11.2 months (1.6 months, not estimable) (HR, 0.49; 95% CI, 0.152, 1.563) in patients with PD‐L1+ tumors and 16.6 months (8.1 months, not estimable) vs 11.2 months (4.2 months, not estimable) (HR, 0.66; 95% CI, 0.296, 1.464) in patients irrespective of PD‐L1 expression. Avelumab + axitinib was efficacious and tolerable in treatment‐naive Japanese patients with advanced RCC, which is consistent with results in the overall population.
Purpose There is limited evidence to support the use of adjuvant chemotherapy (AC) after radical nephroureterectomy (RNU) for upper tract urothelial carcinoma (UTUC). Against this backdrop, we ...hypothesized that such treatment is associated with overall survival (OS) benefit in patients with locally advanced and/or positive regional lymph node disease. Patients and Methods Within the National Cancer Database (2004 to 2012), we identified 3,253 individuals who received AC or observation after RNU for pT3/T4 and/or pN+ UTUC. Inverse probability of treatment weighting (IPTW) -adjusted Kaplan-Meier curves and Cox proportional hazards regression analyses were used to compare OS of patients in the two treatment groups. In addition, we performed exploratory analyses of treatment effect according to age, gender, Charlson comorbidity index, pathologic stage (pT3/T4N0, pT3/T4Nx and pTanyN+), and surgical margin status. Results Overall, 762 (23.42%) and 2,491 (76.58%) patients with pT3/T4 and/or pN+ UTUC received AC and observation, respectively, after RNU. IPTW-adjusted Kaplan-Meier curves showed that median OS was significantly longer for AC versus observation (47.41 interquartile range,19.88 to 112.39 v 35.78 interquartile range, 14.09 to 99.22 months; P < .001). The 5-year IPTW-adjusted rates of OS for AC versus observation were 43.90% and 35.85%, respectively. In IPTW-adjusted Cox proportional hazards regression analysis, AC was associated with a significant OS benefit (hazard ratio, 0.77 95% CI, 0.68 to 0.88; P < .001). This benefit was consistent across all subgroups examined (all P < .05), and no significant heterogeneity of treatment effect was observed (all P
> .05). Conclusion We report an OS benefit in patients who received AC versus observation after RNU for pT3/T4 and/or pN+ UTUC. Although our results are limited by the usual biases related to the observational study design, we believe that the present findings should be considered when advising post-RNU management of advanced UTUC, pending level I evidence.
In metastatic renal-cell carcinoma (mRCC), recent data have shown efficacy of first-line ipilimumab and nivolumab (ipi-nivo) as well as immuno-oncology (IO)/vascular endothelial growth factor (VEGF) ...inhibitor combinations. Comparative data between these strategies are limited.
To compare the efficacy of ipi-nivo versus IO-VEGF (IOVE) combinations in mRCC, and describe practice patterns and effectiveness of second-line therapies.
Using the International Metastatic Renal-cell Carcinoma Database Consortium (IMDC) dataset, patients treated with any first-line IOVE combination were compared with those treated with ipi-nivo.
All patients received first-line IO combination therapies.
First- and second-line response rates, time to treatment failure (TTF), time to next treatment (TNT), and overall survival (OS) were analysed. Hazard ratios were adjusted for IMDC risk factors.
In total, 113 patients received IOVE combinations and 75 received ipi-nivo. For IOVE combinations versus ipi-nivo, first-line response rates were 33% versus 40% (between-group difference 7%, 95% confidence interval CI –8% to 22%, p = 0.4), TTF was 14.3 versus 10.2 mo (p = 0.2), TNT was 19.7 versus 17.9 mo (p = 0.4), and median OS was immature but not statistically different (p = 0.17). Adjusted hazard ratios for TTF, TNT, and OS were 0.71 (95% CI 0.46–1.12, p = 0.14), 0.65 (95% CI 0.38–1.11, p = 0.11), and 1.74 (95% CI 0.82–3.68, p = 0.14), respectively. Sixty-four (34%) patients received second-line treatment. In patients receiving subsequent VEGF-based therapy, second-line response rates were lower in the IOVE cohort than in the ipi-nivo cohort (15% vs 45%; between-group difference 30%, 95% CI 3–57%, p = 0.04; n = 40), though second-line TTF was not significantly different (3.7 vs 5.4 mo; p = 0.4; n = 55). Limitations include the study’s retrospective design and sample size.
There were no significant differences in first-line outcomes between IOVE combinations and ipi-nivo. Most patients received VEGF-based therapy in the second line. In this group, second-line response rate was greater in patients who received ipi-nivo initially.
There were no significant differences in key first-line outcomes for patients with metastatic renal-cell carcinoma receiving immuno-oncology/vascular endothelial growth factor inhibitor combinations versus ipilimumab and nivolumab.
Using the International Metastatic Renal-cell Carcinoma Database Consortium database, we reviewed 188 patients with metastatic renal-cell carcinoma who received first-line ipilimumab and nivolumab (ipi-nivo) versus immuno-oncology/vascular endothelial growth factor (VEGF) combinations. There were no significant differences in first-line outcomes between groups. Response rates to second-line VEGF-based treatments were higher in patients who received ipi-nivo.
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