Neurocognitive functioning and health-related quality of life in adult medulloblastoma patients: long-term outcomes of the NOA-07 study.

BACKGROUND: Combined radiochemotherapy followed by maintenance chemotherapy with cisplatin, lomustine and vincristine within the NOA-07 study resulted in considerable short-term toxicity in adult medulloblastoma patients. Here we investigated the long-term impact of this treatment, focusing on neurocognitive functioning and health-related quality of life (HRQoL). METHODS: Neurocognitive functioning and HRQoL scores over time were determined, and differences between the post-treatment and follow-up assessments were calculated up to 18 months for neurocognition and 60 months for HRQoL. RESULTS: 28/30 patients were analyzed. The three preselected HRQoL scales (role, social and cognitive functioning) showed improved scores, to a clinically relevant extent (≥ 10 points), compared to post-treatment levels up to 30 months, but decreased afterwards. Z-scores for verbal working memory were worse during follow-up compared to post-treatment scores and remained impaired during 18 months follow-up (i.e. z-score below - 1 standard deviation). Attention was impaired post-treatment, and remained impaired to a clinically relevant extent during follow-up. Coordination/processing speed and lexical verbal fluency improved compared to post-treatment scores, and remained within the normal range thereafter. Other tests of verbal fluency were stable over time, with z-scores within the normal range. CONCLUSIONS: This long-term follow-up study showed that the NOA-07 treatment regimen was not associated with a deterioration in HRQoL in the post-treatment period. Verbal working memory deteriorated, while other neurocognitive domains did not seem to be impacted negatively by the treatment.

Information needs and requirements in patients with brain tumours and their relatives.

Patients with brain tumours face a number of medical and social challenges. Previous studies have shown that these patients and their relatives need a high level of patient-oriented information and counselling. However, these needs are often underestimated. In this single-centre cross-sectional study, we evaluated, for the first time, the information needs of patients with brain tumours and their relatives depending on diagnosis, age and level of education. The participants were interviewed using pre-specified questionnaires. Answers were evaluated descriptively using standard statistical methods. A total of 888 questionnaires were sent out. The return rate was 50.7%. The majority of patients (nP = 103; 59.9%) and a higher proportion of relatives (nR = 103; 72.5%; p = 0.019) wished to receive a maximum of information. The majority (79.7% of patients; 83.1% of relatives) also stated that they preferred a personal, face-to-face meeting as primary source of information. The need for information increased with education (p = 0.015), and decreased with tumour grade (p = 0.025) and age (p = 0.118). Our data indicate that patients with brain tumours and their relatives have high information needs throughout their disease and continuously require information and counselling. Optimal provision of information is based on personal preferences, which needs to be evaluated appropriately. Patient-oriented information and counselling are parts of a successful communication strategy that can improve cancer care significantly.

Overcoming the central planner approach - Bilevel optimization of the European energy transition.

The energy transition is a multinational challenge to mitigate climate change, with a joint reduction target for greenhouse gas emissions. Simultaneously, each country is interested in minimizing its own energy supply cost. Still, most energy system models neglect national interests when identifying cost-optimal transition pathways. We design the European energy system transition until 2050, considering competition between countries in a shared electricity and carbon market using bilevel optimization. We find that national objectives substantially impact the transition pathway: Compared to the model solved using the common centralized optimization, the overall installed capacity increases by just 3% when including national interests. However, the distribution of the installed capacity changes dramatically by more than 40% in most countries. Our results underline the risk of miscalculating the need for national capacity expansion when neglecting stakeholder representation in energy system models and demonstrate the need for cooperation for an efficient energy transition.

Transcranial electro-hyperthermia combined with alkylating chemotherapy in patients with relapsed high-grade gliomas: phase I clinical results.

Non-invasive loco-regional electro-hyperthermia (EHT) plus alkylating chemotherapy is occasionally used as salvage treatment in the relapse of patients with high-grade gliomas. Experimental data and retrospective studies suggest potential effects. However, no prospective clinical results are available. We performed a single-center prospective non-controlled single-arm Phase I trial. Main inclusion criteria were recurrent high-grade glioma WHO Grade III or IV, age 18-70, and Karnofsky performance score > or = 70. Primary endpoints were dose-limiting toxicities (DLT) and maximum tolerated dose (MTD) with the combined regimen. Groups of 3 or 4 patients were treated 2-5 times a week in a dose-escalation scheme with EHT. Alkylating chemotherapy (ACNU, nimustin) was administered at a dose of 90 mg/m(2) on day 1 of 42 days for up to six cycles or until tumor progression (PD) or DLT occurred. Fifteen patients with high-grade gliomas were included. Relevant toxicities were local pain and increased focal neurological signs or intracranial pressure. No DLT occurred. In some patients, the administration of mannitol during EHT or long-term use of corticosteroids was necessary to resolve symptoms. Although some patients showed responses in their primarily treated sites, the pattern of response was not well defined. EHT plus alkylating chemotherapy is tolerable in patients with relapse of high-grade gliomas. Episodes of intracranial pressure were, at least, possibly attributed to EHT but did not cause DLTs. A Phase II trial targeting treatment effects is warranted on the basis of the results raised in this trial.

Single-institution cross-sectional study to evaluate need for information and need for referral to psychooncology care in association with depression in brain tumor patients and their family caregivers.

BACKGROUND: The prognosis of patients with brain tumors is widely varying. Psychooncologic need and depression are high among these patients and their family caregivers. However, the need for counselling and need for referral to psychooncology care is often underestimated. METHODS: We performed a single-institution cross-sectional study to evaluate psychooncologic need, depression and information need in both patients and their family caregivers. The Hornheider Screening Instrument (HSI) and the Patient Health Questionnaire (PHQ-9) were used to evaluate psychooncologic need and depression, and a study-specific questionnaire was developed to evaluate information need. Multivariable analyses were performed to detect correlations. RESULTS: A total of 444 patients and their family caregivers were approached to participate, with a survey completion rate of 35.4%. More than half of the patients and family caregivers were in need for referral to psychooncology care and 31.9% of patients suffered from clinically relevant depression. In multivariable analysis, psychooncologic need were positively associated with mild (odds ratio, OR, 7.077; 95% confidence interval, CI, 2.263-22.137; p = 0.001) or moderate to severe (OR 149.27, 95% CI 26.690-737.20; p <  0.001) depression. Patient information need was associated with depression (OR 3.007, 95% CI 1.175-7.695; p = 0.022). CONCLUSIONS: Unmet counselling need in brain tumor patients and their family caregivers associate to high psychooncologic need and depression. Adequate information may decrease the need for referral to psychooncology care and treatment of depression in these patients. Future studies should further explore these relations to promote development of supportive structures.

Multicenter pilot study of radiochemotherapy as first-line treatment for adults with medulloblastoma (NOA-07).

Background: Medulloblastoma in adult patients is rare, with 0.6 cases per million. Prognosis depends on clinical factors and medulloblastoma entity. No prospective data on the feasibility of radiochemotherapy exist. The German Neuro-Oncology Working Group (NOA) performed a prospective descriptive multicenter single-arm phase II trial to evaluate feasibility and toxicity of radio-polychemotherapy. Methods: The NOA-07 trial combined craniospinal irradiation with vincristine, followed by 8 cycles of cisplatin, lomustine, and vincristine. Adverse events, imaging and progression patterns, histological and genetic markers, health-related quality of life (HRQoL), and cognition were evaluated. Primary endpoint was the rate of toxicity-related treatment terminations after 4 chemotherapy cycles, and the toxicity profile. The feasibility goal was reached if at least 45% of patients received at least 4 cycles of maintenance chemotherapy. Results: Thirty patients were evaluable. Each 50% showed classic and desmoplastic/nodular histology. Sixty-seven percent were classified into the sonic hedgehog (SHH) subgroup without TP53 alterations, 13% in wingless (WNT), and 17% in non-WNT/non-SHH. Four cycles of chemotherapy were feasible in the majority (n = 21; 70.0%). Hematological side effects and polyneuropathy were prevalent toxicities. During the active treatment period, HRQoL and verbal fluency improved significantly. The 3-year event-free survival rate was 66.6% at the time of databank lock. Conclusions: Radio-polychemotherapy did lead to considerable toxicity and a high amount of dose reductions throughout the first 4 chemotherapy cycles that may affect efficacy. Thus, we propose frequent patient surveillance using this regimen. Modifications of the regimen may increase feasibility of radio-polychemotherapy of adult patients with medulloblastoma.

High-dose methotrexate prior to simultaneous radiochemotherapy in children with malignant high-grade gliomas.

BACKGROUND: Preradiation chemotherapy including methotrexate (MTX) was effective in children with completely resected high-grade gliomas (HGG). The specific role of MTX remains uncertain. PATIENTS AND METHODS: Children with newly diagnosed HGG and diffuse intrinsic pontine gliomas (DIPG) were enrolled. Two cycles of HD-MTX (5 mg/m2) were given prior to simultaneous radiochemotherapy (SRCT). Response was evaluated two weeks after SRCT. RESULTS: Of 26 children (17 males, median age: 10.3 years) tumor grading was WHO IV (n=9), III (n=10), II/I (n=4, DIPG), unknown (n=3, DIPG). Fourteen tumors were resected. III/IV toxicity after SRCT was: 10/19 anemia, 15/19 leukocytopenia, 12/19 thrombocytopenia, 8/18 infection. No IV infection, gastrointestinal, hepatic or dermal toxicity or toxic death was seen. Stable disease or better was seen in 95.3% (CCR:2, CR:1, PR:8, SD:9, PD:1, unknown:5). CONCLUSION: HD-MTX prior to SRCT is well tolerated and feasible. A randomized trial evaluating the effect of HD-MTX on survival is justified.

Quantitative and qualitative analysis of study-related patient information sheets in randomised neuro-oncology phase III-trials.

INTRODUCTION: In randomised controlled trials (RCTs), patient informed consent documents are an essential cornerstone of the study flow. However, these documents are often oversized in format and content. Clinical experience suggests that study information sheets are often not used as an aid to decision-making due to their complexity. MATERIAL AND METHODS: We analysed nine patient informed consent documents from clinical neuro-oncological phase III-studies running at a German Brain Tumour Centre with the objective to investigate the quality of these documents. Text length, formal layout, readability, application of ethical and legal requirements, scientific evidence and social aspects were used as rating categories. Results were assessed quantitatively by two independents investigators and were depicted using net diagrams. RESULTS: All patient informed consent documents were of insufficient quality in all categories except that ethical and legal requirements were fulfilled. Notably, graduate levels were required to read and understand five of nine consent documents. DISCUSSION: Quality deficits were consistent between the individual study information texts. Irrespective of formal aspects, a document that is intended to inform and motivate patients to participate in a study needs to be well-structured and understandable. We therefore strongly mandate to re-design patient informed consent documents in a patient-friendly way. Specifically, standardised components with a scientific foundation should be provided that could be retrieved at various times, adapted to the mode of treatment and the patient's knowledge, and could weigh information dependent of the stage of treatment decision.

Maintenance treatment with interferon-gamma and low-dose cyclophosphamide for pediatric high-grade glioma.

BACKGROUND: The prognosis of high-grade glioma in children is poor. PURPOSE: Interferon-gamma may increase the immune surveillance of glioma cells. Earlier clinical evidence had shown that low dose cyclophosphamide (CPM) increased immune response. METHODS: After induction treatment with simultaneous radiation and chemotherapy, patients were treated with individually increasing interferon-gamma (IFN-gamma) doses starting from 25 microg/m2/d s.c. increasing up to a maximum of 175 microg/m2/d within 7 weeks. Cyclophosphamide was given at 300 mg/m2 i.v. every 21 days. Forty pediatric glioma patients were enrolled (median age: 8.5 year, male: n = 22). Tumor locations included cerebral cortex (n = 8), basal ganglia (n = 4), brainstem (n = 24), cerebellum (n = 3), spinal cord (n = 1). Histologies were GBM (n = 14), AA (n = 14), LGG (n = 2, diffuse intrinsic pontine glioma). There was grade IV toxicity for thrombocytopenia (10%) and leucopenia (2.5%), grade III toxicity for central nervous (2.5%) and hepatic (5%) side effects, no toxic death. The observation time of the six surviving patients was: 1.2, 1.9, 4.2, 4.4, 4.6 and 4.7 years respectively. The median overall survival (1 year) was not significantly different from a historical control group (0.8 years). The survival of pontine gliomas appeared even inferior when compared to the previous protocol (n.s.). CONCLUSION: Maintenance treatment with IFN-gamma and low dose CPM has no sufficient beneficial effect for the treatment of high-grade glioma.