Laurens V. Beerepoot

Single-agent bevacizumab or lomustine versus a combination of bevacizumab plus lomustine in patients with recurrent glioblastoma (BELOB trial): a randomised controlled phase 2 trial

BACKGROUNDnTreatment options for recurrent glioblastoma are scarce, with second-line chemotherapy showing only modest activity against the tumour. Despite the absence of well controlled trials, bevacizumab is widely used in the treatment of recurrent glioblastoma. Nonetheless, whether the high response rates reported after treatment with this drug translate into an overall survival benefit remains unclear. We report the results of the first randomised controlled phase 2 trial of bevacizumab in recurrent glioblastoma.nnnMETHODSnThe BELOB trial was an open-label, three-group, multicentre phase 2 study undertaken in 14 hospitals in the Netherlands. Adult patients (≥18 years of age) with a first recurrence of a glioblastoma after temozolomide chemoradiotherapy were randomly allocated by a web-based program to treatment with oral lomustine 110 mg/m(2) once every 6 weeks, intravenous bevacizumab 10 mg/kg once every 2 weeks, or combination treatment with lomustine 110 mg/m(2) every 6 weeks and bevacizumab 10 mg/kg every 2 weeks. Randomisation of patients was stratified with a minimisation procedure, in which the stratification factors were centre, Eastern Cooperative Oncology Group performance status, and age. The primary outcome was overall survival at 9 months, analysed by intention to treat. A safety analysis was planned after the first ten patients completed two cycles of 6 weeks in the combination treatment group. This trial is registered with the Nederlands Trial Register (www.trialregister.nl, number NTR1929).nnnFINDINGSnBetween Dec 11, 2009, and Nov 10, 2011, 153 patients were enrolled. The preplanned safety analysis was done after eight patients had been treated, because of haematological adverse events (three patients had grade 3 thrombocytopenia and two had grade 4 thrombocytopenia) which reduced bevacizumab dose intensity; the lomustine dose in the combination treatment group was thereafter reduced to 90 mg/m(2). Thus, in addition to the eight patients who were randomly assigned to receive bevacizumab plus lomustine 110 mg/m(2), 51 patients were assigned to receive bevacizumab alone, 47 to receive lomustine alone, and 47 to receive bevacizumab plus lomustine 90 mg/m(2). Of these patients, 50 in the bevacizumab alone group, 46 in the lomustine alone group, and 44 in the bevacizumab and lomustine 90 mg/m(2) group were eligible for analyses. 9-month overall survival was 43% (95% CI 29-57) in the lomustine group, 38% (25-51) in the bevacizumab group, 59% (43-72) in the bevacizumab and lomustine 90 mg/m(2) group, 87% (39-98) in the bevacizumab and lomustine 110 mg/m(2) group, and 63% (49-75) for the combined bevacizumab and lomustine groups. After the reduction in lomustine dose in the combination group, the combined treatment was well tolerated. The most frequent grade 3 or worse toxicities were hypertension (13 [26%] of 50 patients in the bevacizumab group, three [7%] of 46 in the lomustine group, and 11 [25%] of 44 in the bevacizumab and lomustine 90 mg/m(2) group), fatigue (two [4%], four [9%], and eight [18%]), and infections (three [6%], two [4%], and five [11%]). At the time of this analysis, 144/148 (97%) of patients had died and three (2%) were still on treatment.nnnINTERPRETATIONnThe combination of bevacizumab and lomustine met prespecified criteria for assessment of this treatment in further phase 3 studies. However, the results in the bevacizumab alone group do not justify further studies of this treatment.nnnFUNDINGnRoche Nederland and KWF Kankerbestrijding.

Identification of Patients with Recurrent Glioblastoma Who May Benefit from Combined Bevacizumab and CCNU Therapy: A Report from the BELOB Trial

The results from the randomized phase II BELOB trial provided evidence for a potential benefit of bevacizumab (beva), a humanized monoclonal antibody against circulating VEGF-A, when added to CCNU chemotherapy in patients with recurrent glioblastoma (GBM). In this study, we performed gene expression profiling (DASL and RNA-seq) of formalin-fixed, paraffin-embedded tumor material from participants of the BELOB trial to identify patients with recurrent GBM who benefitted most from beva+CCNU treatment. We demonstrate that tumors assigned to the IGS-18 or classical subtype and treated with beva+CCNU showed a significant benefit in progression-free survival and a trend toward benefit in overall survival, whereas other subtypes did not exhibit such benefit. In particular, expression of FMO4 and OSBPL3 was associated with treatment response. Importantly, the improved outcome in the beva+CCNU treatment arm was not explained by an uneven distribution of prognostically favorable subtypes as all molecular glioma subtypes were evenly distributed along the different study arms. The RNA-seq analysis also highlighted genetic alterations, including mutations, gene fusions, and copy number changes, within this well-defined cohort of tumors that may serve as useful predictive or prognostic biomarkers of patient outcome. Further validation of the identified molecular markers may enable the future stratification of recurrent GBM patients into appropriate treatment regimens.

The impact of bevacizumab on health-related quality of life in patients treated for recurrent glioblastoma: Results of the randomised controlled phase 2 BELOB trial

BACKGROUNDnThe BELOB study, a randomised controlled phase 2 trial comparing lomustine, bevacizumab and combined lomustine and bevacizumab in patients with recurrent glioblastoma, showed that the 9-month overall survival rate was most promising in the combination arm. Here we report the health-related quality of life (HRQoL) results, a secondary trial end-point.nnnMETHODSnHRQoL was measured at baseline and every 6weeks until progression using the European Organisation for Research and Treatment of Cancer (EORTC) core questionnaire (QLQ-C30) and brain module (QLQ-BN20). HRQoL was assessed over time for five preselected scales (global health (GH), physical (PF) and social functioning (SF), motor dysfunction (MD) and communication deficit (CD)). Moreover, mean changes in HRQoL from baseline until progression were determined.nnnRESULTSn138/148 patients with at least a baseline HRQoL assessment were analysed. Over time, HRQoL remained relatively stable in all treatment arms for all five scales, at least during the first three treatment cycles. More than half (54-61%) of the patients showed stable (<10 point change) or improved (⩾10 point change) HRQoL during their progression-free time, except for SF (43%), irrespective of treatment arm. Deterioration of mean HRQoL was most profound at disease progression for all scales except SF, which deteriorated earlier in disease course. Compared to baseline, 40% of patients had clinically relevant (⩾10 points) worse GH, PF and SF, while 44% and 31% had increased MD and CD at disease progression, irrespective of treatment arm.nnnCONCLUSIONSnBevacizumab, whether or not in combination with lomustine, did not negatively affect HRQoL in patients treated for recurrent glioblastoma in this randomised study.

Perioperative treatment and radical cystectomy for bladder cancer--a population based trend analysis of 10,338 patients in the Netherlands.

BACKGROUNDnIn Europe, population-based data concerning perioperative treatment (PT) and radical cystectomy (RC) are lacking. We assessed temporal trends in PT (neoadjuvant chemotherapy [NAC], neoadjuvant radiotherapy [NAR], adjuvant chemotherapy [AC], adjuvant radiotherapy [AR]) and RC in the Netherlands and identified patients and hospital characteristics associated with PT.nnnMETHODSnThis nationwide, retrospective, population-based study included cTa/is, T1-4, N0-3, M0-1 bladder cancer patients from the Netherlands Cancer Registry who underwent RC with curative intent between 1995 and 2013. PT-administration over time was compared with chi-square tests. Multivariable logistic regression analyses were performed to identify characteristics associated with PT usage. The sub-groups cT2-4N0M0 and cT2-4, N0 or NX, M0 or MX were separately analysed.nnnRESULTSnIn total, 10,338 patients met inclusion criteria. Eighty-six percent did not receive PT, 7.0% received NAC (or induction chemotherapy [IC]), 3.2% NAR, 1.8% AC, and 2.1% AR. NAC usage increased from 0.6% in 1995 to 21% in 2013 (p < 0.001), application of NAR decreased from 15% to 0.4% (p < 0.001). Usage of AC and AR in 2013 was <1.5%. Comparable temporal trends were found in 6032 patients staged cT2-4N0M0. Multivariable logistic regression analysis revealed that younger age, ≥ cT3, ≥ cN1 and treatment in academic/teaching hospitals were associated with NAC or IC (all p < 0.05).nnnCONCLUSIONSnThe increase in NAC administration in the Netherlands reflects a slow but steady adoption of evidence-based guidelines over the last two decades. Considerable variability in patients and hospital characteristics in the likelihood of receiving NAC exists. Conversely, NAR, AR and AC are hardly administered anymore.

Prognostic value and kinetics of circulating endothelial cells in patients with recurrent glioblastoma randomised to bevacizumab plus lomustine, bevacizumab single agent or lomustine single agent. A report from the Dutch Neuro-Oncology Group BELOB trial

Background:Angiogenesis is crucial for glioblastoma growth, and anti-vascular endothelial growth factor agents are widely used in recurrent glioblastoma patients. The number of circulating endothelial cells (CECs) is a surrogate marker for endothelial damage. We assessed their kinetics and explored their prognostic value in patients with recurrent glioblastoma.Methods:In this side study of the BELOB trial, 141 patients with recurrent glioblastoma were randomised to receive single-agent bevacizumab or lomustine, or bevacizumab plus lomustine. Before treatment, after 4 weeks and after 6 weeks of treatment, CECs were enumerated.Results:The number of CECs increased during treatment with bevacizumab plus lomustine, but not during treatment in the single-agent arms. In patients treated with lomustine single agent, higher absolute CEC numbers after 4 weeks (log10CEC hazard ratio (HR) 0.41, 95% CI 0.18–0.91) and 6 weeks (log10CEC HR 0.16, 95% CI 0.05–0.56) of treatment were associated with improved overall survival (OS). Absolute CEC numbers in patients receiving bevacizumab plus lomustine or bevacizumab single agent were not associated with OS.Conclusion:CEC numbers increased during treatment with bevacizumab plus lomustine but not during treatment with either agent alone, suggesting that this combination induced the greatest vascular damage. Although the absolute number of CECs was not associated with OS in patients treated with bevacizumab either alone or in combination, they could serve as a marker in glioblastoma patients receiving lomustine single agent.

Pathological downstaging and survival after induction chemotherapy and radical cystectomy for clinically node-positive bladder cancer—Results of a nationwide population-based study

BACKGROUNDnInduction chemotherapy (IC) for clinically node-positive bladder cancer is applied without clinical evidence of improved outcome. Our objective was to compare complete pathological downstaging (pCD) and overall survival (OS) for IC versus upfront radical cystectomy (RC) in cT1-4aN1-3M0 urothelial carcinoma (UC).nnnMETHODSnThis population-based study included 659xa0cN+xa0patients treated with RC between 1995 and 2013. IC was applied in 212 (32%) patients. We defined pCD as ≤(y)pT1N0 at RC. Multivariable analyses were preformed to identify independent predictors of pCD and OS.nnnRESULTSnIn cN1 and cN2-3 patients, 31% and 19% of patients proved to be pN0 at upfront RC. In cN1, pCD was achieved in 39% following IC versus 5% for upfront RC (Pxa0<xa00.001). In cN2-3 UC, rates were 27% versus 3% (Pxa0<xa00.001). Three-year OS for pCD and ypCD were 81% and 84%, respectively. Three-year OS rates were 66% versus 37% (cN1) and 43% versus 22% (cN2-3), again in favour of IC (Pxa0<xa00.001). In multivariable analyses, IC was associated with pCD (Odds ratio, 14; 95% confidence interval [CI], 7.4-25) and a 53% decreased risk of death (Hazard ratio [HR], 0.47; 95% CI, 0.36-0.61). Indication bias and unequal distributions of factors associated with OS (e.g. patients proceeding to RC) limit interpretation of our results.nnnCONCLUSIONSnPatients with clinical nodal involvement should not be neglected. Up to 1/4 of patients with cN+xa0disease had pN0 at upfront RC. Moreover, IC followed by RC for clinically node-positive UC was associated with improved pathological downstaging compared with RC alone. A potential OS benefit for IC needs to be validated in a randomised trial.nnnTAKE HOME MESSAGEnIC followed by RC for clinically node-positive UC is associated with improved pathological downstaging compared with RC alone. A potential OS benefit for IC needs to be validated in a randomised trial.

Age-related systemic treatment and survival of patients with metachronous metastases from colorectal cancer

Abstract Background: Although the spectrum of systemic treatment for metastatic colorectal cancer (mCRC) has widened, there is a paucity of evidence for the feasibility and optimal use of these systemic agents in elderly patients. The present study provides real world data on the age-related systemic treatment and survival of CRC patients with non-resectable metachronous metastases. Methods: All consecutive patients with non-resectable metastases from primary resected CRC were extracted from the Eindhoven area of the Netherlands Cancer Registry (NCR). Patients receiving palliative systemic therapy were enrolled (nu2009=u2009385). Systemic treatment and survival were analyzed according to age at diagnosis of metastases. Results: Patients agedu2009≥75 years more often received first-line single-agent chemotherapy than their younger counterparts (63% vs. 32%, pu2009<u2009.0001). First-line single-agent chemotherapy was often prescribed without additional targeted therapy (78%). Advanced age (≥75 years) was associated with a lower probability of receiving all active cytotoxic agents compared to patients aged <60 years at time of diagnosis of metastases (odds ratio (OR) 0.2, 95% CI 0.10–0.77). In a multivariable Cox regression analysis with adjustment for age and other relevant prognostic factors, the total number of received systemic agents was the only predictor of death (hazard ratio (HR) 0.7, 95% CI 0.61–0.81). Conclusion: The beneficial effect of treatment with all active systemic agents on survival (simultaneously or sequentially prescribed) should be taken into account when considering systemic therapy in patients with mCRC. In light of our results, future studies are warranted to clarify the role of potential targeted therapy in elderly mCRC patients, who are often not candidates for combination chemotherapy and treatment with all active cytotoxic agents.

Superior efficacy of neoadjuvant chemotherapy and radical cystectomy in cT3-4aN0M0 compared to cT2N0M0 bladder cancer: Superior efficacy of neoadjuvant chemotherapy and radical cystectomy

In this study, we compared complete pathological downstaging (pCD, ≤(y)pT1N0) and overall survival (OS) in patients with cT2 versus cT3–4aN0M0 UC of the bladder undergoing radical cystectomy (RC) with or without neoadjuvant chemo‐ (NAC) or radiotherapy (NAR). A population‐based sample of 5,517 patients, who underwent upfront RC versus NAC + RC or NAR + RC for cT2‐4aN0M0 UC between 1995–2013, was identified from the Netherlands Cancer Registry. Data were retrieved from individual patient files and pathology reports. pCD‐rates were compared using Chi‐square tests and OS was estimated by Kaplan–Meier analyses. Multivariable analyses were conducted to determine odds (OR) and hazard ratios (HR) for pCD‐status and OS, respectively. We included 4,504 (82%) patients with cT2 and 1,013 (18%) with cT3–4a UC. Median follow‐up was 9.2 years. In cT2 UC, pCD‐rate was 25% after upfront RC versus 43% (p < 0.001) and 33% (p = 0.130) after NAC + RC and NAR + RC, respectively. In cT3–4a UC, pCD‐rate was 8% after upfront RC versus 37% (p < 0.001) and 16% (p = 0.281) after NAC + RC and NAR + RC, respectively. In cT2 UC, 5‐year OS was 57% and 51% for NAC + RC and upfront RC, respectively (p = 0.135), whereas in cT3–4a UC, 5‐year OS was 55% for NAC + RC versus 36% for upfront RC (p < 0.001). In multivariable analysis for OS, NAC was beneficial in cT3–4a UC (HR: 0.67, 95%CI 0.51–0.89) but not in cT2 UC (HR: 0.91, 95%CI 0.72–1.15). NAR did not influence OS. In conclusion, NAC + RC was associated with superior pCD compared to RC alone and NAR + RC. Superior OS for NAC + RC compared to RC alone was especially evident in cT3–4a disease.

Perioperatieve behandelingen en radicale cystectomie voor blaaskanker. Een trendanalyse over 10.338 patiënten in Nederland

SamenvattingAchtergrondIn Europa zijn epidemiologische data betreffende perioperatieve behandelingen (PB) en radicale cystectomie (RC) niet voorhanden. Wij onderzochten trends in de toepassing van neoadjuvante chemotherapie (NAC), neoadjuvante radiotherapie (NAR), adjuvante chemotherapie (AC) en adjuvante radiotherapie (AR) en RC in een bepaalde periode in Nederland. Tevens onderzochten wij patiënt- en ziekenhuisfactoren die geassocieerd waren met PB.MethodenIn deze landelijke, retrospectieve studie werden alle patiënten uit de Nederlandse Kanker Registratie (NKR) geïncludeerd, die een RC met curatieve intentie ondergingen voor cTa/is, T1–4, N0–3, M0–1 blaaskanker (BK) tussen 1995 en 2013. De toepassing van PB in de loop van de tijd werd vergeleken met de uitkomst van Chi-kwadraattesten. Multivariabele logistische regressieanalyses werden uitgevoerd om karakteristieken te identificeren die zijn geassocieerd met PB. De subgroepen cT2–4, N0 of Nx, M0 of Mx en cT2–4N0M0 werden afzonderlijk geanalyseerd.ResultatenIn totaal werden 10.338 patiënten geïncludeerd. 86u2009% onderging geen PB, 7,0u2009% ontving NAC (of inductiechemotherapie (IC)), 3,2u2009% NAR, 1,8u2009% AC en 2,1u2009% AR. De toepassing van NAC steeg van 0,6u2009% in 1995 naar 21u2009% in 2013 (pxa0< 0,001), de toepassing van NAR daalde van 15u2009% naar 0,4u2009% (pxa0< 0,001). AC en AR werden in 2013 in <1,5u2009% van de gevallen toegepast. Vergelijkbare trends werden gezien bij 6.032 cT2–4N0M0 BK-patiënten. Multivariabele logistische regressieanalyse toonde dat een lagere leeftijd, ≥cT3, ≥cN1 en behandeling in academische en opleidingsziekenhuizen geassocieerd waren met de toepassing van NAC (inclusief IC) (alle pxa0< 0,05).ConclusieDe stijging in de toepassing van NAC in de laatste twee decennia toont een langzame, maar gestage adaptatie van internationale richtlijnen in Nederland. Betreffende de toepassing van NAC bestaan er aanzienlijke variaties in patiënt- en ziekenhuiskarakteristieken. In tegenstelling tot NAC worden NAR, AR en AC nauwelijks (meer) toegepast.AbstractBackgroundIn Europe, population-based data concerning perioperative treatment (PT) and radical cystectomy (RC) are lacking. We assessed temporal tends in PT (neoadjuvant chemotherapy (NAC), neoadjuvant radiotherapy (NAR), adjuvant chemotherapy (AC), adjuvant radiotherapy (AR)) and RC in the Netherlands and identified patients’ and hospital characteristics associated with PT.MethodsThis nationwide, retrospective, population-based study included cTa/is, T1–4, N0–3, M0–1 bladder cancer (BC) patients from the Netherlands Cancer Registry who underwent RC with curative intent between 1995 and 2013. PT-administration over time was compared with chi-square tests. Multivariable logistic regression analyses were performed to identify characteristics associated with PT usage. The sub-groups cT2–4N0M0 and cT2–4, N0 or Nx, M0 or Mx were separately analyzed.ResultsIn total, 10,338 patients met inclusion criteria. 86xa0% did not receive PT, 7.0u2009% received NAC (or induction chemotherapy (IC)), 3.2u2009% NAR, 1.8u2009% AC, and 2.1u2009% AR. NAC usage increased from 0.6xa0% in 1995 to 21.2u2009% in 2013 (pxa0< 0.001), application of NAR decreased from 15.1xa0% to 0.4xa0% (pxa0< 0.001). Usage of AC and AR in 2013 was <1.5u2009%. Comparable temporal trends were found in 6,032 patients staged cT2–4N0M0. Multivariable logistic regression analysis revealed that younger age, ≥cT3, ≥cN1 and treatment in academic/teaching hospitals were associated with NAC or IC (all pxa0< 0.05).ConclusionsThe increase in NAC administration in the Netherlands reflects axa0slow but steady adoption of evidence based guidelines over the last two decades. Considerable variability in patients’ and hospital characteristics in the likelihood of receiving NAC exists. Conversely, NAR, AR and AC are hardly administered anymore.

NIMG-13. RADIOLOGICAL RESPONSE ASSESSMENT IN THE ERA OF BEVACIZUMAB: RANO OR VOLUMETRY? A REPORT FROM THE BELOB TRIAL

Purpose: nResponse assessment in brain tumors is currently done with the 2D Response Assessment in Neuro-Oncology (RANO) criteria. However, bevacizumab-treated patients may show pseudoresponse on contrast enhanced T1w- (T1w+C), and more infiltrative growth on T2w/FLAIR images at recurrence. We assessed whether in recurrent glioblastoma volumetric methods improve assessment of progressive disease (PD) over the RANO criteria, by correlating PD with overall survival (OS), the golden endpoint in oncology studies.