Martin J. B. Taphoorn

Symptom management in glioma patients remains a challenge, as patients suffer from various concurrent occurring symptoms. This study aimed to identify symptom clusters and to examine the relation between these symptom clusters and functioning. We prospectively included individual patient data from previously published international randomized controlled trials (RCTs) in glioma patients. Symptom prevalence and level of functioning were assessed with EORTC QLQ-C30 and QLQ-BN20 questionnaires. The magnitude of the associations between symptoms were examined with Spearman correlation coefficients and correlation matrices. Hierarchical cluster analyses (looking at euclidean distances) were performed to identify symptom clusters. Multivariable regression analyses were performed to analyze associations between the symptom clusters and functioning, adjusted for confounding variables. Data of 3595 newly diagnosed glioma patients who completed the questionnaires before randomization indicated that many patients (44%) suffered from 5–10 symptoms simultaneously. The most prevalent symptoms were fatigue, drowsiness and motor dysfunction, experienced by 86%, 59% and 55% of the patients respectively. Five symptom clusters were identified with hierarchical cluster analyses: motor cluster, fatigue cluster, headache cluster, gastrointestinal/seizures cluster and hair loss/itchy skin cluster. Having symptoms in the motor cluster had a clinically relevant and significant negative influence (≥10points difference) on the global health status/quality of life scale, and physical, role, cognitive and social functioning (Beta’s ranged from -10.9 to -18.6, all p<0.001). Similarly, having symptoms in the fatigue cluster had a clinically relevant negative influence on the global health status/quality of life scale, and role and social functioning (Beta’s ranged from -10.7 to -15.5, all p<0.001) CONCLUSIONS: Two symptom clusters, the fatigue and motor cluster, were frequently affected in glioma patients and demonstrated to negatively influence functioning and global quality of life. Implementation of interventions targeting fatigue and motor problems would therefore contribute to improved functioning and quality of life in glioma patients.

2009 Background: Although bevacizumab (BEV) is frequently used in recurrent grade II and III glioma without 1p/19q co-deletion, this use is without evidence from randomized trials. Methods: The TAVAREC trial (NCT01164189) is a randomized phase II study in locally diagnosed non-1p/19q co-deleted grade II or III glioma, with a first and contrast-enhancing recurrence after initial radiotherapy. Prior chemotherapy was allowed provided patients were at least 6 months off treatment. Patients were treated with either 200mg/m² temozolomide (TMZ) day 1-5 every 4 weeks for a maximum of twelve cycles, or with the same TMZ regimen in combination with BEV 10 mg/kg every 2 weeks until progression. Response, Quality of Life (QOL, using the EORTC QOL C30/BCM20 questionnaire) and neurocognitive function (NCF) using a standardized test battery with Hopkins Verbal Learning, Trail Making test A/B and Controlled Oral Word Association were evaluated every 3 months. Primary endpoint is the Overall Survival (OS) rate at 12 months (OS12). Tumor samples were centrally analyzed for MGMT status (Illumina methylation arrays) and IDH1/2 mutations ( IDHmt). Results: Between 8/2/2011 and 31/7/2015, 155 patients were randomized; median age was 44 years, 88 (70%) of 125 tested tumors showed an IDHmt, 27% of patients had received prior chemotherapy. OS12 was 61% in the TMZ arm and 55% in the TMZ+BEV arm, with overlapping OS and progression free survival (PFS) Kaplan Meier curves and similar response rates (TMZ: 42%; TMZ + BEV: 49%). Post-progression, 33% of the TMZ and 17% of the TMZ + BEV patients received BEV. OS was longer in IDHmt tumors compared to IDH wild type tumors (15 mo vs 10.7 mo, p = 0.001) but PFS was clinically similar (6.7 mo vs 5.1 mo, p = 0.056). IDH mutational status was not predictive for benefit to BEV. Compliance to NCF testing and QOL was above 60% in the 1^st year. At the group level, NCF was similar in the TMZ and in the TMZ+BEV patients. QOL and MGMTresults will be presented at the meeting. Conclusions: The addition of BEV to TMZ does not improve OS, PFS, or cognitive function in recurrent grade II and III 1p/19q intact gliomas; regardless of IDH mutational status. Clinical trial information: NCT01164189.

2001 Background: Phase II data from BELOB suggested the combination of bevacizumab and lomustine to produce an overall survival (OS) benefit for patients with progressive glioblastoma. EORTC 26101 aimed investigating whether the combination of bevacizumab and lomustine improves OS in patients with first progression of a glioblastoma compared to lomustine alone. Methods: Patients with progressive disease after standard chemoradiation at least 3 months off the concomitant part were randomized 2:1 between lomustine 90 mg/m² (cap. 160 mg with toxicity-driven escalation to cap. 200 mg from cycle 2 on) every six weeks plus 10 mg/kg bevacizumab every two weeks and lomustine single agent 110 mg/m²(cap. 200 mg) every six weeks followed by best investigators choice at further progression. Targeted hazard ratio (HR) was 0.72 for the comparison of OS as the primary endpoint. Progression-free survival (PFS) was an important secondary endpoint. Neuroimaging according to a standard protocol was assessed locally and centrally. Results: A total of 437 (288 and 149, respectively) patients were included. Median number of treatment cycles was 1 in the lomustine arm and 3 in the combination arm. With 329 OS events (75.3%) OS was not superior in the combination therapy arm (HR 0.95 (confidence interval (CI) 0.74, 1.21), p = 0.650, analyses stratified by EORTC online randomization system), whereas locally assessed PFS was longer with the addition of bevacizumab to lomustine (HR 0.49 (CI 0.39, 0.61). Median efficacy outcomes were: OS 9.1 (8.1, 10.1) versus 8.6 (7.6, 10.4) months and PFS 4.2 (3.7, 4.3) versus 1.5 (1.5, 2.5) months in the combination arm versus the lomustine arm, respectively. Toxicity was in the expected range with more events in the combination arm being also longer on treatment. Crossover to bevacizumab occurred in 35.5% of patients in the control arm; whereas 19% of patients in the combination arm continued bevacizumab at progression. Conclusions: Bevacizumab treatment in patients with progressive glioblastoma despite prolonged PFS does not confer a survival advantage. Future molecular and neuroimaging research should identify those patients deriving benefit from that treatment. Clinical trial information: NCT01290939.

Purpose As glioblastoma progresses, patients experience a decline in health-related quality of life (HRQoL). Delaying this decline is an important treatment goal. In newly diagnosed glioblastoma, progression-free survival was prolonged when bevacizumab was added to radiotherapy plus temozolomide (RT/TMZ) versus placebo plus RT/TMZ (phase III AVAglio study; hazard ratio, 0.64; 95% CI, 0.55 to 0.74; P < .001). To ensure that addition of bevacizumab to standard-of-care therapy was not associated with HRQoL detriment, HRQoL assessment was a secondary objective. Patients and Methods Patients completed European Organisation for Research and Treatment of Cancer Quality of Life Questionnaires C30 and BN20 at each tumor assessment (Appendix Table A1, online only). Raw scores were converted to a 100-point scale and mean changes from baseline scores were evaluated (stable: < 10-point change; clinically relevant deterioration/improvement: ≥ 10-point change). Deterioration-free survival was the time to deterioration/progression/death; time to deterioration was the time to deterioration/death. Results Most evaluable patients who had not progressed (> 74%) completed all HRQoL assessments for at least 1 year of treatment, and almost all completed at least one HRQoL assessment at baseline (98.3% and 97.6%, bevacizumab and placebo arms, respectively). Mean changes from baseline did not reach a clinically relevant difference between arms for most items. HRQoL declined at progression in both arms. The addition of bevacizumab to RT/TMZ resulted in statistically longer (P < .001) deterioration-free survival across all items. Time to deterioration was not statistically longer in the placebo plus RT/TMZ arm (v bevacizumab) for any HRQoL item. Conclusion The addition of bevacizumab to standard-of-care treatment for newly diagnosed glioblastoma had no impact on HRQoL during the progression-free period.

Several outcome measures are available to evaluate the benefit of a specific treatment strategy in clinical trials for brain tumor patients. Traditional outcome measures are progression-free survival and overall survival as well as the radiological response assessed on magnetic resonance imaging (MRI). Equally important, patient-centered outcomes are available that focus on outcome measures reflecting patient functioning, symptoms, and health-related quality of life (HRQOL).

Every cancer treatment, irrespective of its clinical effectiveness, has an impact on patients’ quality of life (QoL). Even recently developed targeted therapies might have side effects and significantly impact patients’ QoL. Thus, understanding the advantages and disadvantages of different treatments from the patient’s standpoint has become a must in clinical research and is highly valued by major stakeholders. Thousands of cancer patients are enrolled into randomized controlled trials (RCTs) each year and many complete patient-reported outcome (PRO) instruments to obtain patient-centered information as part of the assessment of the overall effectiveness of the new therapy. Some of these RCTs have generated high quality PRO evidence forming the basis for approval (or support to approval) of drugs by the US Food and Drug Administration. However, a consistent strategy to determine the quality of patient centered evidence presented in RCTs has until recently been lacking. One of the fundamental questions when including PROs in clinical research revolves around methodological robustness and consistency of outcome reporting. Cancer patients, physicians and healthcare system stakeholders need to rely on solid information to make the best possible choice regarding treatment. Therefore generating high-quality findings from PRO assessment in cancer trials is of paramount importance. In an effort to improve quality of PRO assessment and reporting in the near future, the Patient-Reported Outcome Measurements Over Time In ONcology (PROMOTION) Registry was developed. The scope of this Registry is to identify, track, analyse, and store information on all cancer RCTs that have included PROs, and assess the quality of their PRO assessments.