Adjuvant Nivolumab versus Placebo in Muscle-Invasive Urothelial Carcinoma.

BACKGROUND: The role of adjuvant treatment in high-risk muscle-invasive urothelial carcinoma after radical surgery is not clear. METHODS: In a phase 3, multicenter, double-blind, randomized, controlled trial, we assigned patients with muscle-invasive urothelial carcinoma who had undergone radical surgery to receive, in a 1:1 ratio, either nivolumab (240 mg intravenously) or placebo every 2 weeks for up to 1 year. Neoadjuvant cisplatin-based chemotherapy before trial entry was allowed. The primary end points were disease-free survival among all the patients (intention-to-treat population) and among patients with a tumor programmed death ligand 1 (PD-L1) expression level of 1% or more. Survival free from recurrence outside the urothelial tract was a secondary end point. RESULTS: A total of 353 patients were assigned to receive nivolumab and 356 to receive placebo. The median disease-free survival in the intention-to-treat population was 20.8 months (95% confidence interval [CI], 16.5 to 27.6) with nivolumab and 10.8 months (95% CI, 8.3 to 13.9) with placebo. The percentage of patients who were alive and disease-free at 6 months was 74.9% with nivolumab and 60.3% with placebo (hazard ratio for disease recurrence or death, 0.70; 98.22% CI, 0.55 to 0.90; P<0.001). Among patients with a PD-L1 expression level of 1% or more, the percentage of patients was 74.5% and 55.7%, respectively (hazard ratio, 0.55; 98.72% CI, 0.35 to 0.85; P<0.001). The median survival free from recurrence outside the urothelial tract in the intention-to-treat population was 22.9 months (95% CI, 19.2 to 33.4) with nivolumab and 13.7 months (95% CI, 8.4 to 20.3) with placebo. The percentage of patients who were alive and free from recurrence outside the urothelial tract at 6 months was 77.0% with nivolumab and 62.7% with placebo (hazard ratio for recurrence outside the urothelial tract or death, 0.72; 95% CI, 0.59 to 0.89). Among patients with a PD-L1 expression level of 1% or more, the percentage of patients was 75.3% and 56.7%, respectively (hazard ratio, 0.55; 95% CI, 0.39 to 0.79). Treatment-related adverse events of grade 3 or higher occurred in 17.9% of the nivolumab group and 7.2% of the placebo group. Two treatment-related deaths due to pneumonitis were noted in the nivolumab group. CONCLUSIONS: In this trial involving patients with high-risk muscle-invasive urothelial carcinoma who had undergone radical surgery, disease-free survival was longer with adjuvant nivolumab than with placebo in the intention-to-treat population and among patients with a PD-L1 expression level of 1% or more. (Funded by Bristol Myers Squibb and Ono Pharmaceutical; CheckMate 274 ClinicalTrials.gov number, NCT02632409.).

Treatment of muscle-invasive urothelial cancer with nivolumab (CheckMate 274 study): a plain language summary.

WHAT IS THIS SUMMARY ABOUT?: This is a summary of a paper published in a medical journal that describes the results of a study called CheckMate 274. This study looked at a new treatment for muscle-invasive urothelial cancer, a type of cancer found in the urinary tract that has spread from the inner lining of the urinary tract or bladder and into the surrounding muscle wall where it can then spread to other parts of the body. The standard treatment for muscle-invasive urothelial cancer is surgery to remove affected parts of the urinary tract. However, cancer returns in more than half of people after this surgery. Adjuvant therapy is given to people after surgery with muscle-invasive urothelial cancer with a goal to reduce the risk of the cancer coming back; however, at the time this study started, there was no standard adjuvant treatment. WHAT HAPPENED IN THE STUDY?: In the CheckMate 274 study, researchers compared nivolumab with a placebo as an adjuvant treatment for people with muscle-invasive urothelial cancer. The aim of the study was to understand how well nivolumab worked to reduce the chance of the cancer returning after surgery. The study also looked at what side effects (unwanted or unexpected results or conditions that are possibly related to the use of a medication) people had with treatment. WHAT DO THE RESULTS MEAN?: The results showed that people who received nivolumab versus placebo: Survived longer before the cancer was detected again, including people who had programmed death ligand-1 (shortened to PD-L1) on their cancer cells. Survived longer before a secondary cancer outside of the urinary tract was detected. Experienced no differences in health-related quality of life (the impact of the treatment on a person's mental and physical health). Had similar side effects to the people who received nivolumab in other studies. Clinical Trial Registration: NCT02632409 (ClinicalTrials.gov).

Adjuvant nivolumab versus placebo following radical surgery for high-risk muscle-invasive urothelial carcinoma: a subgroup analysis of Japanese patients enrolled in the phase 3 CheckMate 274 trial.

BACKGROUND: The phase 3 CheckMate 274 trial demonstrated superiority of adjuvant nivolumab over placebo after radical surgery in patients with high-risk muscle-invasive urothelial carcinoma. However, the efficacy and safety of adjuvant nivolumab in Japanese patients with muscle-invasive urothelial carcinoma have not been clarified. METHODS: Patients with muscle-invasive urothelial carcinoma were randomized to adjuvant nivolumab 240 mg or placebo (every 2 weeks via intravenous infusion) up to 120 days after radical surgery in CheckMate 274. RESULTS: Of 49 patients in the Japanese subgroup, 27 and 22 patients were randomized to nivolumab and placebo, respectively. Eleven and 8 patients, respectively, had tumor PD-L1 expression level of 1% or more. The median disease-free survival times in the nivolumab and placebo groups were 29.67 months (95% confidence interval 7.79-not reached) and 9.72 months (95% confidence interval 4.73-not reached), respectively (hazard ratio 0.77, 95% confidence interval 0.35-1.69). The corresponding values in patients with tumor PD-L1 expression level of 1% or more were 29.67 months (95% confidence interval 2.63-not reached) and 25.95 months (95% confidence interval 5.59-not reached) (hazard ratio 1.10, 95% confidence interval 0.31-3.92), respectively. Treatment-related adverse events of Grade 3-4 occurred in 25.9 and 13.6% of patients in the nivolumab and placebo groups, respectively. The most common treatment-related adverse events in the nivolumab group were lipase increased, amylase increased and diarrhea. The changes in quality of life scores from baseline over time were similar in both groups. CONCLUSIONS: The efficacy and safety results in the Japanese subgroup were consistent with the overall population of CheckMate 274.

Nivolumab in patients with unresectable locally advanced or metastatic urothelial carcinoma: CheckMate 275 2-year global and Japanese patient population analyses.

BACKGROUND: Nivolumab has demonstrated antitumor activity and manageable safety in the single-arm, phase II CheckMate 275 study in patients with unresectable locally advanced or metastatic platinum-resistant urothelial carcinoma. We report updated results of the global population and a subanalysis of Japanese patients from this study. METHODS: Patients received nivolumab 3 mg/kg intravenously every 2 weeks until progression or unacceptable toxicity. The primary endpoint was objective response rate (ORR) confirmed by blinded independent review committee (BIRC) per Response Evaluation Criteria in Solid Tumors v1.1. Secondary endpoints included progression-free survival (PFS) by BIRC and overall survival (OS). Safety was also reported. The minimum follow-up was 21 months. RESULTS: Overall, 270 patients were treated with nivolumab globally; 23 patients were Japanese. In the global and Japanese populations, respectively, ORR per BIRC was 20.4% and 21.7%; median PFS was 1.9 (95% confidence interval [CI] 1.9-2.3) and 3.8 months (95% CI 1.9-7.2); and median OS was 8.6 (95% CI 6.1-11.3) and 21.0 months (95% CI 7.2-not reached). The most common any grade treatment-related adverse events were fatigue (18.1%) and diarrhea (12.2%) in the global population; the most common in the Japanese population were diarrhea (26.1%) and pyrexia (13.0%). Grade 3 or 4 treatment-related adverse events occurred in 61 (22.6%) and seven (30.4%) of the global and Japanese patients, respectively. CONCLUSIONS: Nivolumab continues to show antitumor activity and survival in the global population of CheckMate 275. Meaningful clinical benefit was also observed in Japanese patients. No new safety signals were identified.

Internal Mammary and Medial Supraclavicular Irradiation in Breast Cancer.

BACKGROUND: The effect of internal mammary and medial supraclavicular lymph-node irradiation (regional nodal irradiation) added to whole-breast or thoracic-wall irradiation after surgery on survival among women with early-stage breast cancer is unknown. METHODS: We randomly assigned women who had a centrally or medially located primary tumor, irrespective of axillary involvement, or an externally located tumor with axillary involvement to undergo either whole-breast or thoracic-wall irradiation in addition to regional nodal irradiation (nodal-irradiation group) or whole-breast or thoracic-wall irradiation alone (control group). The primary end point was overall survival. Secondary end points were the rates of disease-free survival, survival free from distant disease, and death from breast cancer. RESULTS: Between 1996 and 2004, a total of 4004 patients underwent randomization. The majority of patients (76.1%) underwent breast-conserving surgery. After mastectomy, 73.4% of the patients in both groups underwent chest-wall irradiation. Nearly all patients with node-positive disease (99.0%) and 66.3% of patients with node-negative disease received adjuvant systemic treatment. At a median follow-up of 10.9 years, 811 patients had died. At 10 years, overall survival was 82.3% in the nodal-irradiation group and 80.7% in the control group (hazard ratio for death with nodal irradiation, 0.87; 95% confidence interval [CI], 0.76 to 1.00; P=0.06). The rate of disease-free survival was 72.1% in the nodal-irradiation group and 69.1% in the control group (hazard ratio for disease progression or death, 0.89; 95% CI, 0.80 to 1.00; P=0.04), the rate of distant disease-free survival was 78.0% versus 75.0% (hazard ratio, 0.86; 95% CI, 0.76 to 0.98; P=0.02), and breast-cancer mortality was 12.5% versus 14.4% (hazard ratio, 0.82; 95% CI, 0.70 to 0.97; P=0.02). Acute side effects of regional nodal irradiation were modest. CONCLUSIONS: In patients with early-stage breast cancer, irradiation of the regional nodes had a marginal effect on overall survival. Disease-free survival and distant disease-free survival were improved, and breast-cancer mortality was reduced. (Funded by Fonds Cancer; ClinicalTrials.gov number, NCT00002851.).

Results from a Phase I Study of Lapatinib with Gemcitabine and Cisplatin in Advanced or Metastatic Bladder Cancer: EORTC Trial 30061.

BACKGROUND/OBJECTIVE: Lapatinib is a potent HER1 and HER2 inhibitor. Gemcitabine-cisplatin (GC) is a standard chemotherapy regimen for advanced/metastatic bladder cancer. This phase I study examined the safety of lapatinib in combination with GC in patients with bladder cancer. The primary aim was to determine the maximum tolerated dose (MTD) of lapatinib in combination with GC. METHODS: A 3 + 3 dose escalation protocol was used with lapatinib at 750, 1,000 and then 1,250 mg. It was dosed daily with gemcitabine (1,000 mg/m2 on days 1, 8 and 15) and cisplatin (70 mg/m2 on day 2) every 28 days. In all, 18 patients with a median age of 63 years (range 50-77) were included; 3/6, 3/5 and 6/7 patients received lapatinib at 750, 1,000 and 1,250 mg, combined with GC, in cohorts 1, 2 and 3, respectively. RESULTS: No dose-limiting toxicities (DLTs) were observed in cohort 1 or 2 (3 patients each); in cohort 3 (2 × 3 patients), 1 of the 6 patients presented DLTs (grade 4, treatment-related febrile neutropenia and renal failure). Twelve patients received 6 cycles. CONCLUSIONS: Lapatinib at 750-1,250 mg combined with GC appears safe and tolerable. The MTD of lapatinib combined with GC in bladder cancer was 1,250 mg.

A risk management approach for imaging biomarker-driven clinical trials in oncology.

Imaging has steadily evolved in clinical cancer research as a result of improved conventional imaging methods and the innovation of new functional and molecular imaging techniques. Despite this evolution, the design and data quality derived from imaging within clinical trials are not ideal and gaps exist with paucity of optimised methods, constraints of trial operational support, and scarce resources. Difficulties associated with integrating imaging biomarkers into trials have been neglected compared with inclusion of tissue and blood biomarkers, largely because of inherent challenges in the complexity of imaging technologies, safety issues related to new imaging contrast media, standardisation of image acquisition across multivendor platforms, and various postprocessing options available with advanced software. Ignorance of these pitfalls directly affects the quality of the imaging read-out, leading to trial failure, particularly when imaging is a primary endpoint. Therefore, we propose a practical risk-based framework and recommendations for trials driven by imaging biomarkers, which allow identification of risks at trial initiation to better allocate resources and prioritise key tasks.

Whole-breast irradiation with or without a boost for patients treated with breast-conserving surgery for early breast cancer: 20-year follow-up of a randomised phase 3 trial.

BACKGROUND: Since the introduction of breast-conserving treatment, various radiation doses after lumpectomy have been used. In a phase 3 randomised controlled trial, we investigated the effect of a radiation boost of 16 Gy on overall survival, local control, and fibrosis for patients with stage I and II breast cancer who underwent breast-conserving treatment compared with patients who received no boost. Here, we present the 20-year follow-up results. METHODS: Patients with microscopically complete excision for invasive disease followed by whole-breast irradiation of 50 Gy in 5 weeks were centrally randomised (1:1) with a minimisation algorithm to receive 16 Gy boost or no boost, with minimisation for age, menopausal status, presence of extensive ductal carcinoma in situ, clinical tumour size, nodal status, and institution. Neither patients nor investigators were masked to treatment allocation. The primary endpoint was overall survival in the intention-to-treat population. The trial is registered with ClinicalTrials.gov, number NCT02295033. FINDINGS: Between May 24, 1989, and June 25, 1996, 2657 patients were randomly assigned to receive no radiation boost and 2661 patients randomly assigned to receive a radiation boost. Median follow-up was 17.2 years (IQR 13.0-19.0). 20-year overall survival was 59.7% (99% CI 56.3-63.0) in the boost group versus 61.1% (57.6-64.3) in the no boost group, hazard ratio (HR) 1.05 (99% CI 0.92-1.19, p=0.323). Ipsilateral breast tumour recurrence was the first treatment failure for 354 patients (13%) in the no boost group versus 237 patients (9%) in the boost group, HR 0.65 (99% CI 0.52-0.81, p<0.0001). The 20-year cumulative incidence of ipsilatelal breast tumour recurrence was 16.4% (99% CI 14.1-18.8) in the no boost group versus 12.0% (9.8-14.4) in the boost group. Mastectomies as first salvage treatment for ipsilateral breast tumour recurrence occurred in 279 (79%) of 354 patients in the no boost group versus 178 (75%) of 237 in the boost group. The cumulative incidence of severe fibrosis at 20 years was 1.8% (99% CI 1.1-2.5) in the no boost group versus 5.2% (99% CI 3.9-6.4) in the boost group (p<0.0001). INTERPRETATION: A radiation boost after whole-breast irradiation has no effect on long-term overall survival, but can improve local control, with the largest absolute benefit in young patients, although it increases the risk of moderate to severe fibrosis. The extra radiation dose can be avoided in most patients older than age 60 years. FUNDING: Fonds Cancer, Belgium.

Retrospective quality control review of FDG scans in the imaging sub-study of PALETTE EORTC 62072/VEG110727: a randomized, double-blind, placebo-controlled phase III trial.

PURPOSE: (18)F-Labelled fluorodeoxyglucose (FDG) can detect early changes in tumour metabolism and may be a useful quantitative imaging biomarker (QIB) for prediction of disease stabilization, response and duration of progression-free survival (PFS). Standardization of imaging procedures is a prerequisite, especially in multicentre clinical trials. In this study we reviewed the quality of FDG scans and compliance with the imaging guideline (IG) in a phase III clinical trial. METHODS: Forty-four cancer patients were enroled in an imaging sub-study of a randomized international multicentre trial. FDG scan had to be performed at baseline and 10-14 days after treatment start. The image transmittal forms (ITFs) and Digital Imaging and Communications in Medicine (DICOM) [1] standard headers were analysed for compliance with the IG. Mean liver standardized uptake values (LSUVmean) were measured as recommended by positron emission tomography (PET) Response Criteria in Solid Tumors 1.0 (PERCIST) [2]. RESULTS: Of 88 scans, 81 were received (44 patients); 36 were properly anonymized; 77/81 serum glucose values submitted, all but one within the IG. In 35/44 patients both scans were of sufficient visual quality. In 22/70 ITFs the reported UT differed by >1 min from the DICOM headers (max. difference 1 h 4 min). Based on the DICOM, UT compliance for both scans was 31.4%. LSUVmean was fairly constant for the 11 patients with UT compliance: 2.30 ± 0.33 at baseline and 2.27 ± 0.48 at follow-up (FU). Variability substantially increased for the subjects with unacceptable UT (11 patients): 2.27 ± 1.04 at baseline and 2.18 ± 0.83 at FU. CONCLUSION: The high attrition number of patients due to low compliance with the IG compromised the quantitative assessment of the predictive value for early response monitoring. This emphasizes the need for better regulated procedures in imaging departments, which may be achieved by education of involved personnel or efforts towards regulations. LSUVmean could be monitored to assess quality and compliance in an FDG PET/CT study.

Concordance measures in shared frailty models: application to clustered data in cancer prognosis.

Frailty models are gaining interest in prognostic studies, especially because of the spread of multicenter studies. However, little research has been performed to extend prognostic tools to frailty models, including discrimination measures. As previously performed for the Harrell's c-index, we extended two different discrimination measures (the model-based concordance probability estimation of Gönen and Heller and the nonparametric Uno's c-index) to take into account cluster membership. We calculate measures at three levels: between-group, where only patients with different frailties are compared, within-group, where only patients sharing the same frailty are compared, and overall. We performed simulations to study the impact of group size and the number of groups on these measures. Results showed that the two measures can be extended to frailty models while remaining independent from censoring distribution, provided that the group size is sufficient. We apply the extended measures to two real datasets, a meta-analysis and a large multicenter trial.

Meta-Analysis of the Test-Retest Repeatability of [18F]-Fluorodeoxyglucose Standardized Uptake Values: Implications for Assessment of Tumor Response.

PURPOSE: Currently, guidelines for PET with 18F-fluorodeoxyglucose (FDG-PET) interpretation for assessment of therapy response in oncology primarily involve visual evaluation of FDG-PET/CT scans. However, quantitative measurements of the metabolic activity in tumors may be even more useful in evaluating response to treatment. Guidelines based on such measurements, including the European Organization for Research and Treatment of Cancer Criteria and PET Response Criteria in Solid Tumors, have been proposed. However, more rigorous analysis of response criteria based on FDG-PET measurements is needed to adopt regular use in practice. EXPERIMENTAL DESIGN: Well-defined boundaries of repeatability and reproducibility of quantitative measurements to discriminate noise from true signal changes are a needed initial step. An extension of the meta-analysis from de Langen and colleagues (2012) of the test-retest repeatability of quantitative FDG-PET measurements, including mean, maximum, and peak standardized uptake values (SUVmax, SUVmean, and SUVpeak, respectively), was performed. Data from 11 studies in the literature were used to estimate the relationship between the variance in test-retest measurements with uptake level and various study-level, patient-level, and lesion-level characteristics. RESULTS: Test-retest repeatability of percentage fluctuations for all three types of SUV measurement (max, mean, and peak) improved with higher FDG uptake levels. Repeatability in all three SUV measurements varied for different lesion locations. Worse repeatability in SUVmean was also associated with higher tumor volumes. CONCLUSIONS: On the basis of these results, recommendations regarding SUV measurements for assessing minimal detectable changes based on repeatability and reproducibility are proposed. These should be applied to differentiate between response categories for a future set of FDG-PET-based criteria that assess clinically significant changes in tumor response.

Disease-free Survival Analysis for Patients with High-risk Muscle-invasive Urothelial Carcinoma from the Randomized CheckMate 274 Trial by PD-L1 Combined Positive Score and Tumor Cell Score.

BACKGROUND: The CheckMate 274 trial demonstrated improved disease-free survival (DFS) with adjuvant nivolumab versus placebo in patients with muscle-invasive urothelial carcinoma at high risk of recurrence after radical surgery in both the intent-to-treat population and the subset with tumor programmed death ligand 1 (PD-L1) expression ≥1%. OBJECTIVE: To analyze DFS by combined positive score (CPS), which is based on PD-L1 expression in both tumor and immune cells. DESIGN, SETTING, AND PARTICIPANTS: We randomized a total of 709 patients 1:1 to nivolumab 240 mg or placebo every 2 wk intravenously for ≤1 yr of adjuvant treatment. INTERVENTION: Nivolumab 240 mg. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Primary endpoints were DFS in the intent-to-treat population and patients with tumor PD-L1 expression ≥1% using the tumor cell (TC) score. CPS was determined retrospectively from previously stained slides. Tumor samples with both quantifiable CPS and TC were analyzed. RESULTS AND LIMITATIONS: Of 629 patients evaluable for CPS and TC, 557 (89%) had CPS ≥1, 72 (11%) had CPS <1, 249 (40%) had TC ≥1%, and 380 (60%) had TC <1%. Among patients with TC <1%, 81% (n = 309) had CPS ≥1. DFS was improved with nivolumab versus placebo for patients with TC ≥1% (hazard ratio [HR] 0.50, 95% confidence interval [CI] 0.35-0.71), those with CPS ≥1 (HR 0.62, 95% CI 0.49-0.78), and patients with both TC <1% and CPS ≥1 (HR 0.73, 95% CI 0.54-0.99). CONCLUSION: More patients had CPS ≥1 than TC ≥1%, and most patients who had TC <1% had CPS ≥1. In addition, patients with CPS ≥1 experienced improved DFS with nivolumab. These results may, in part, explain the mechanisms underlying a benefit with adjuvant nivolumab even in patients who had both TC <1% and CPS ≥1. PATIENT SUMMARY: We studied survival time without cancer recurrence (disease-free survival; DFS) for patients treated with nivolumab versus placebo after surgery to remove the bladder or components of the urinary tract for bladder cancer in the CheckMate 274 trial. We assessed the impact of levels of the protein PD-L1 expressed either on tumor cells (tumor cell score; TC) or on both tumor cells and immune cells surrounding the tumor (combined positive score; CPS). DFS was impoved with nivolumab versus placebo for patients with TC ≥1%, CPS ≥1, and for patients with both TC <1% and CPS ≥1. This analysis may help physicians understand which patients would benefit most from treatment with nivolumab.

Nivolumab in Patients with Advanced Platinum-resistant Urothelial Carcinoma: Efficacy, Safety, and Biomarker Analyses with Extended Follow-up from CheckMate 275.

PURPOSE: We report efficacy and safety with extended follow-up, and exploratory biomarker analyses from the phase II CheckMate 275 trial to identify biomarkers of response to nivolumab in platinum-resistant metastatic or unresectable urothelial carcinoma (mUC). PATIENTS AND METHODS: Patients received nivolumab 3 mg/kg once every 2 weeks until disease progression, unacceptable toxicity, or other protocol-defined reasons. The primary endpoint was objective response rate (ORR) per blinded independent review committee (BIRC; using RECIST v1.1) in all treated patients and by tumor PD-L1 expression. Key secondary endpoints were progression-free survival (PFS) per BIRC using RECIST v1.1 and overall survival (OS) in all patients and by PD-L1 expression. Exploratory endpoints included safety and biomarker analyses of tumor mutational burden (TMB), PD-L1, and previously identified mutational signatures. RESULTS: Of 270 treated patients, 139 had evaluable TMB. With 33.7 months' minimum follow-up, ORR per BIRC, median PFS, and median OS [95% confidence interval (CI)] in all treated patients were 20.7% (16.1-26.1), 1.9 months (1.9-2.3), and 8.6 months (6.1-11.3), respectively. No new safety signals were identified. Higher TMB was associated (P < 0.05) with improved ORR [OR (95% CI): 2.13 (1.26-3.60)], PFS [HR: 0.75 (0.61-0.92)], and OS [HR: 0.73 (0.58-0.91)]. TMB combined with PD-L1 better predicted ORR, PFS, and OS than PD-L1 alone. Higher mutational signature 2 score was associated with better OS but did not improve the predictive value of TMB. CONCLUSIONS: These results support the durable antitumor activity of nivolumab and suggest that TMB may enrich for better response in mUC. Future studies of TMB/PD-L1 as biomarkers for response to nivolumab in randomized trials are warranted.See related commentary by Swami et al., p. 5059.

Repeatability and reproducibility of relative cerebral blood volume measurement of recurrent glioma in a multicentre trial setting.

BACKGROUND: Measurement of relative cerebral blood volume (rCBV) with dynamic susceptibility contrast (DSC) magnetic resonance imaging (MRI) is used extensively for brain tumour diagnosis and follow-up. The aim of this pilot study was to assess the robustness of rCBV measurement in patients with enhancing recurrent glioma in a European multicentre trial setting. METHODS: We included pre-treatment postcontrast T1 weighted (T1w) and DSC scans of 20 patients with recurrent glioma from 2 European Organisation for Research and Treatment of Cancer trials (26101 and 26091). Three reviewers independently placed a fixed circular region of interest of 70 mm2 in the tumour area of highest rCBV (rCBVmax). To calculate the normalised rCBVmax (nrCBVmax), three ROIs were placed in the anterior, middle and posterior centrum semiovale normal-appearing white matter of the contralateral hemisphere. After several months, each observer repeated the assessments blinded for initial findings. Repeatability and reproducibility were estimated with a mixed model. Each measurement was also classified according to 4 clinically meaningful categories. RESULTS: Three patients were post hoc excluded from analysis because of lack of enhancing tumour. The mean nrCBVmax repeatability was 49.5%, and reproducibility was 5.5%. In 14 of 17 patients, at least 2 reviewers classified the patient into the same category. CONCLUSIONS: Our results indicate that a well-established review process needs to be applied upfront to assess perfusion in a multicentre trial setting. While awaiting further validation, we propose as a strategy to measure rCBV in the context of recurrent glioma trials to use two central reviewers and an adjudicator in case of disagreement.

Comparison of Local Control of Brain Metastases With Stereotactic Radiosurgery vs Surgical Resection: A Secondary Analysis of a Randomized Clinical Trial.

Importance: Brain metastases are a common source of morbidity for patients with cancer, and limited data exist to support the local therapeutic choice between surgical resection and stereotactic radiosurgery (SRS). Objective: To evaluate local control of brain metastases among patients treated with SRS vs surgical resection within the European Organization for the Research and Treatment of Cancer (EORTC) 22952-26001 phase 3 trial. Design, Setting, and Participants: This unplanned, exploratory analysis of the international, multi-institutional randomized clinical trial EORTC 22952-26001 (conducted from 1996-2007) was performed from February 9, 2017, through July 25, 2018. The EORTC 22952-26001 trial randomized patients with 1 to 3 brain metastases to whole-brain radiotherapy vs observation after complete surgical resection or before SRS. Patients in the present analysis were stratified but not randomized according to local modality (SRS or surgical resection) and treated per protocol with 1 to 2 brain metastases and tumors with a diameter of no greater than 4 cm. Interventions: Surgical resection or SRS. Main Outcomes and Measures: The primary end point was local recurrence of treated lesions. Cumulative incidence of local recurrence was calculated according to modality (surgical resection vs SRS) with competing risk regression to adjust for prognostic factors and competing risk of death. Results: A total of 268 patients were included in the analysis (66.4% men; median age, 60.7 years [range, 26.9-81.1 years]); 154 (57.5%) underwent SRS and 114 (42.5%) underwent surgical resection. Median follow-up time was 39.9 months (range, 26.0-1982.0 months). Compared with the SRS group, patients undergoing surgical resection had larger metastases (median 28 mm [range, 10-40 mm] vs 20 mm [range, 4-40 mm]; P < .001), more frequently had 1 brain metastasis (112 [98.2%] vs 114 [74.0%]; P < .001), and differed in location (parietal, 21 [18.4%] vs 61 [39.6%]; posterior fossa, 30 [26.3%] vs 12 [7.8%]; P < .001). In adjusted models, local recurrence was similar between the SRS and surgical resection groups (hazard ratio [HR], 1.15; 95% CI, 0.72-1.83). However, when stratified by interval, patients with surgical resection had a much higher risk of early (0-3 months) local recurrence compared with those undergoing SRS (HR, 5.94; 95% CI, 1.72-20.45), but their risk decreased with time (HR for 3-6 months, 1.37 [95% CI, 0.64-2.90]; HR for 6-9 months, 0.75 [95% CI, 0.28-2.00]). At 9 months or longer, the surgical resection group had a lower risk of local recurrence (HR, 0.36; 95% CI, 0.14-0.93). Conclusions and Relevance: In this exploratory analysis, local control of brain metastases was similar between SRS and surgical resection groups. Stereotactic radiosurgery was associated with improved early local control of treated lesions compared with surgical resection, although the relative benefit decreased with time. Trial Registration: ClinicalTrials.gov Identifier: NCT00002899.

Comparison of Immediate vs Deferred Cytoreductive Nephrectomy in Patients With Synchronous Metastatic Renal Cell Carcinoma Receiving Sunitinib: The SURTIME Randomized Clinical Trial.

Importance: In clinical practice, patients with primary metastatic renal cell carcinoma (mRCC) have been offered cytoreductive nephrectomy (CN) followed by targeted therapy, but the optimal sequence of surgery and systemic therapy is unknown. Objective: To examine whether a period of sunitinib therapy before CN improves outcome compared with immediate CN followed by sunitinib. Design, Setting, and Participants: This randomized clinical trial began as a phase 3 trial on July 14, 2010, and continued until March 24, 2016, with a median follow-up of 3.3 years and a clinical cutoff date for this report of May 5, 2017. Patients with mRCC of clear cell subtype, resectable primary tumor, and 3 or fewer surgical risk factors were studied. Interventions: Immediate CN followed by sunitinib therapy vs treatment with 3 cycles of sunitinib followed by CN in the absence of progression followed by sunitinib therapy. Main Outcomes and Measures: Progression-free survival was the primary end point, which needed a sample size of 458 patients. Because of poor accrual, the independent data monitoring committee endorsed reporting the intention-to-treat 28-week progression-free rate (PFR) instead. Overall survival (OS), adverse events, and postoperative progression were secondary end points. Results: The study closed after 5.7 years with 99 patients (80 men and 19 women; mean [SD] age, 60 [8.5] years). The 28-week PFR was 42% in the immediate CN arm (n = 50) and 43% in the deferred CN arm (n = 49) (P = .61). The intention-to-treat OS hazard ratio of deferred vs immediate CN was 0.57 (95% CI, 0.34-0.95; P = .03), with a median OS of 32.4 months (95% CI, 14.5-65.3 months) in the deferred CN arm and 15.0 months (95% CI, 9.3-29.5 months) in the immediate CN arm. In the deferred CN arm, 48 of 49 patients (98%; 95% CI, 89%-100%) received sunitinib vs 40 of 50 (80%; 95% CI, 67%-89%) in the immediate arm. Systemic progression before planned CN in the deferred CN arm resulted in a per-protocol recommendation against nephrectomy in 14 patients (29%; 95% CI, 18%-43%). Conclusions and Relevance: Deferred CN did not improve the 28-week PFR. With the deferred approach, more patients received sunitinib and OS results were higher. Pretreatment with sunitinib may identify patients with inherent resistance to systemic therapy before planned CN. This evidence complements recent data from randomized clinical trials to inform treatment decisions in patients with primary clear cell mRCC requiring sunitinib. Trial Registration: ClinicalTrials.gov identifier: NCT01099423.

Surgical Safety of Cytoreductive Nephrectomy Following Sunitinib: Results from the Multicentre, Randomised Controlled Trial of Immediate Versus Deferred Nephrectomy (SURTIME).

The European Organisation for Research and Treatment of Cancer SURTIME trial explored timing of sunitinib, a tyrosine kinase inhibitor (TKI), and cytoreductive nephrectomy (CN) in patients with metastatic renal cell carcinoma. Previous retrospective studies suggest increased surgery-related adverse events (AEs) after presurgical TKI. We report surgical safety from a randomised comparison of CN before or after sunitinib. In-hospital mortality, 30-d readmission rate, and intraoperative and 30-d postoperative AEs according to Common Terminology Criteria for Adverse Events version 4 and Clavien-Dindo (CD) were analysed. Patients were randomised 1:1 to immediate CN followed by sunitinib versus sunitinib followed by deferred CN 24h after the last dose of sunitinib. None of the tumours in the deferred arm became unresectable, and only two patients had a sunitinib-related delay of CN of >2wk. AEs related to surgery (all grades) in the immediate and deferred arms occurred in 52% and 53% after CN, respectively, although the number of intraoperative surgery-related AEs was higher in the immediate arm. Postoperative AEs (CD ≥3), 30-d readmission, and in-hospital mortality rates were 6.5%, 13%, and 4.3% in the immediate arm and 2.5%, 7.5%, and 2.5% in the deferred arm, respectively. There were no differences in surgery time, blood loss, and hospital stay. PATIENT SUMMARY: Patients with metastatic kidney cancer do not have more surgical complications irrespective of whether they are treated with systemic therapy before or after surgery.