Stable glioma incidence and increased patient survival over the past two decades in Norway: a nationwide registry-based cohort study.

BACKGROUND: Surveillance of incidence and survival of central nervous system tumors is essential to monitor disease burden and epidemiological changes, and to allocate health care resources. Here, we describe glioma incidence and survival trends by histopathology group, age, and sex in the Norwegian population. MATERIAL AND METHODS: We included patients with a histologically verified glioma reported to the Cancer Registry of Norway from 2002 to 2021 (N = 7,048). Population size and expected mortality were obtained from Statistics Norway. Cases were followed from diagnosis until death, emigration, or 31 December 2022, whichever came first. We calculated age-standardized incidence rates (ASIR) per 100,000 person-years and age-standardized relative survival (RS).  Results: The ASIR for histologically verified gliomas was 7.4 (95% CI: 7.3-7.6) and was higher for males (8.8; 95% CI: 8.5-9.1) than females (6.1; 95% CI: 5.9-6.4). Overall incidence was stable over time. Glioblastoma was the most frequent tumor entity (ASIR = 4.2; 95% CI: 4.1-4.4). Overall, glioma patients had a 1-year RS of 63.6% (95% CI: 62.5-64.8%), and a 5-year RS of 32.8% (95% CI: 31.6-33.9%). Females had slightly better survival than males. For most entities, 1- and 5-year RS improved over time (5-year RS for all gliomas 29.0% (2006) and 33.1% (2021), p < 0.001). Across all tumor types, the RS declined with increasing age at diagnosis. INTERPRETATION: The incidence of gliomas has been stable while patient survival has increased over the past 20 years in Norway. As gliomas represent a heterogeneous group of primary CNS tumors, regular reporting from cancer registries at the histopathology group level is important to monitor disease burden and allocate health care resources in a population.

Investigating survival, quality of life and cognition in PROton versus photon therapy for IDH-mutated diffuse grade 2 and 3 GLIOmas (PRO-GLIO): a randomised controlled trial in Norway and Sweden.

INTRODUCTION: The use of proton therapy increases globally despite a lack of randomised controlled trials demonstrating its efficacy and safety. Proton therapy enables sparing of non-neoplastic tissue from radiation. This is principally beneficial and holds promise of reduced long-term side effects. However, the sparing of seemingly non-cancerous tissue is not necessarily positive for isocitrate dehydrogenase (IDH)-mutated diffuse gliomas grade 2-3, which have a diffuse growth pattern. With their relatively good prognosis, yet incurable nature, therapy needs to be delicately balanced to achieve a maximal survival benefit combined with an optimised quality of life. METHODS AND ANALYSIS: PRO-GLIO (PROton versus photon therapy in IDH-mutated diffuse grade 2 and 3 GLIOmas) is an open-label, multicentre, randomised phase III non-inferiority study. 224 patients aged 18-65 years with IDH-mutated diffuse gliomas grade 2-3 from Norway and Sweden will be randomised 1:1 to radiotherapy delivered with protons (experimental arm) or photons (standard arm). First intervention-free survival at 2 years is the primary endpoint. Key secondary endpoints are fatigue and cognitive impairment, both at 2 years. Additional secondary outcomes include several survival measures, health-related quality of life parameters and health economy endpoints. ETHICS AND DISSEMINATION: To implement proton therapy as part of standard of care for patients with IDH-mutated diffuse gliomas grade 2-3, it should be deemed safe. With its randomised controlled design testing proton versus photon therapy, PRO-GLIO will provide important information for this patient population concerning safety, cognition, fatigue and other quality of life parameters. As proton therapy is considerably more costly than its photon counterpart, cost-effectiveness will also be evaluated. PRO-GLIO is approved by ethical committees in Norway (Regional Committee for Medical & Health Research Ethics) and Sweden (The Swedish Ethical Review Authority) and patient inclusion has commenced. Trial results will be published in international peer-reviewed journals, relevant conferences, national and international meetings and expert forums. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov Registry (NCT05190172).

Continuous prostate-specific antigen rise despite salvage radiotherapy following radical prostatectomy: Pattern of clinical relapse and predictive factors.

Salvage radiotherapy for post-prostatectomy biochemical recurrence does not always control the disease. It would be useful to identify patients who would not benefit from radiotherapy to the prostate bed prior to making treatment recommendations. One such group of patients is those who experience continuously rising prostate-specific antigen (PSA) despite radiotherapy. The purpose of this study was to identify risk factors for continuous PSA increase and the pattern of radiological relapse during follow-up. We performed a retrospective comparison of two patient groups with PSA decline or continuous increase following salvage radiotherapy to the prostate bed. All patients received 3-D conformal radiotherapy (35 fractions of 2 Gy). Patients with continuous PSA increase were more likely to have had complete surgical resection (negative margins) and a shorter interval to radiotherapy (<24 months). However, the only statistically significant risk factor was Gleason score. Sixty-four percent of patients with a Gleason score of 9 developed continuously increasing PSA, indicating that residual subclinical cancer was not located in the prostate bed. The median time to radiological recurrence was 43 months. Isolated pelvic nodal recurrence was uncommon. Almost all patients with radiological recurrence had high-risk disease, in particular stage pT3. In conclusion, the majority of patients with biologically aggressive tumors with Gleason score 9 were not adequately treated with prostate bed radiotherapy alone. The predominant pattern of radiological recurrence was outside of the pelvis. Therefore, the problem of distant micrometastases has to be addressed.

Impact of systemic treatment on survival after whole brain radiotherapy in patients with brain metastases.

Most patients with brain metastases have active extracranial disease, which limits survival unless effective systemic therapy can be administered. Available options have increased over the last 5 years. Therefore, we analyzed patient cohorts treated with or without systemic treatment after completion of whole brain radiotherapy (WBRT). This study included retrospective uni- and multivariate analyses of 189 patients. Two landmark analyses requiring minimum survival of 1 or 2 months from start of WBRT were performed. Age and Karnofsky performance status (KPS) requirements were also applied in order to resemble a prospective trial that would limit inclusion to patients with defined baseline characteristics such as adequate KPS. Irrespective of these different statistical scenarios, systemic treatment significantly improved survival. For example, the 2-month landmark analysis with upper age limit and inclusion of patients with KPS > 60 only showed median survival of 9.0 versus 3.7 months, p = 0.001. All patients alive after more than 2 years had received systemic treatment (chemotherapy, endocrine therapy, tyrosine kinase inhibitors or other drugs). After WBRT, systemic treatment is a prerequisite for long-term survival. The exact magnitude of improvement can only be assessed in randomized trials because retrospective cohort studies, even if carefully designed, are not able to correct for all potential imbalances.

A semiautomatic tool for prostate segmentation in radiotherapy treatment planning.

BACKGROUND: Delineation of the target volume is a time-consuming task in radiotherapy treatment planning, yet essential for a successful treatment of cancers such as prostate cancer. To facilitate the delineation procedure, the paper proposes an intuitive approach for 3D modeling of the prostate by slice-wise best fitting ellipses. METHODS: The proposed estimate is initialized by the definition of a few control points in a new patient. The method is not restricted to particular image modalities but assumes a smooth shape with elliptic cross sections of the object. A training data set of 23 patients was used to calculate a prior shape model. The mean shape model was evaluated based on the manual contour of 10 test patients. The patient records of training and test data are based on axial T1-weighted 3D fast-field echo (FFE) sequences. The manual contours were considered as the reference model. Volume overlap (Vo), accuracy (Ac) (both ratio, range 0-1, optimal value 1) and Hausdorff distance (HD) (mm, optimal value 0) were calculated as evaluation parameters. RESULTS: The median and median absolute deviation (MAD) between manual delineation and deformed mean best fitting ellipses (MBFE) was Vo (0.9 ± 0.02), Ac (0.81 ± 0.03) and HD (4.05 ± 1.3)mm and between manual delineation and best fitting ellipses (BFE) was Vo (0.96 ± 0.01), Ac (0.92 ± 0.01) and HD (1.6 ± 0.27)mm. Additional results show a moderate improvement of the MBFE results after Monte Carlo Markov Chain (MCMC) method. CONCLUSIONS: The results emphasize the potential of the proposed method of modeling the prostate by best fitting ellipses. It shows the robustness and reproducibility of the model. A small sample test on 8 patients suggest possible time saving using the model.

Towards improved prognostic scores predicting survival in patients with brain metastases: a pilot study of serum lactate dehydrogenase levels.

Accurate prognostic information is desirable when counselling patients with brain metastases regarding their therapeutic options and life expectancy. Based on previous studies, we selected serum lactate dehydrogenase (LDH) as a promising factor on which we perform a pilot study investigating methodological aspects of biomarker studies in patients with brain metastases, before embarking on large-scale studies that will look at a larger number of candidate markers in an expanded patient cohort. For this retrospective analysis, 100 patients with available information on LDH treated with palliative whole-brain radiotherapy were selected. A comprehensive evaluation of different LDH-based variables was performed in uni- and multivariate tests. Probably, the most intriguing finding was that LDH kinetics might be more important, or at least complement, information obtained from a single measurement immediately before radiotherapy. LDH and performance status outperformed several other variables that are part of prognostic models such as recursive partitioning analyses classes and graded prognostic assessment score. LDH kinetics might reflect disease behaviour in extracranial metastatic and primary sites without need for comprehensive imaging studies and is a quite inexpensive diagnostic test. Based on these encouraging results, confirmatory studies in a larger cohort of patients are warranted.

Non-small cell lung cancer histological subtype has prognostic impact in patients with brain metastases.

In patients with brain metastases from non-small cell lung cancer, the prognostic impact of primary tumour histology, a feature with increasing implications for choice of systemic therapy, is not well defined. Therefore, a multi-institutional analysis was performed: retrospective uni- and multivariate analyses in 209 patients treated with different approaches including surgery and radiosurgery. While squamous cell and large cell carcinoma patients had comparable survival, those with adenocarcinoma survived significantly longer. In multivariate models, adenocarcinoma histology was confirmed as independent prognostic factor, which complements both recursive partitioning analysis (RPA) classes and diagnosis-specific graded prognostic assessment (GPA). When evaluated together with primary tumour control, extracranial metastases, number of brain metastases, age and performance status as individual covariates rather than RPA or GPA score, adenocarcinoma histology again emerged as significant prognostic factor. A significant but small survival advantage for patients with adenocarcinoma was evident already in the time period before drugs such as pemetrexed and epidermal growth factor receptor tyrosine kinase inhibitors were available. However, the gap has widened in recently treated patients. Comparable to patients without brain metastases, primary tumour histology should be taken into account when assessing patients' prognosis and recommending treatment strategy.

Can current prognostic scores reliably guide treatment decisions in patients with brain metastases from malignant melanoma?

PURPOSE: We evaluated the performance of the new 4-tiered melanoma-specific graded prognostic assessment (GPA) score and the previously published general GPA score in patients with brain metastases from malignant melanoma managed with different approaches including best supportive care. MATERIALS AND METHODS: Retrospective analysis of 51 patients. Compared with the original analysis of the melanoma-specific GPA score, these patients were more representative of the general population of patients with brain metastases from this disease. RESULTS: The present data confirmed that both scores identify patients with favorable prognosis who might be candidates for focal treatments. However, survival in the 2 unfavorable prognostic subgroups defined by the melanoma-specific GPA was not significantly different. Median survival in the melanoma-specific GPA classes was 3.1, 3.7, 7.5, and 12.7 months. Karnofsky performance status (KPS) and serum lactatdehydrogenase (LDH) level significantly predicted survival. CONCLUSION: In order to select the right patient to the right treatment and avoid overtreatment and suboptimal resource utilization in patients with very limited survival, improved prognostic tools are needed. The melanoma-specific GPA does not include extracranial disease extent or surrogate markers such as LDH. We suggest that a combination of KPS <70 and elevated LDH might better predict short survival than any of the GPA scores. This hypothesis should be confirmed in larger studies.

Postoperative treatment and prognosis of patients with resected single brain metastasis: how useful are established prognostic scores?

OBJECTIVE: To evaluate postoperative prognosis and the performance of known prognostic scores in patients treated with surgical resection for single brain metastasis. METHODS: We evaluated prognostic factors and five previously published prognostic scores in a group of 74 patients with single brain metastasis treated with surgery with or without immediate whole-brain radiotherapy (WBRT). RESULTS: In multivariate analysis, good performance status, absence of extracranial metastases and primary tumor control were significantly associated with improved overall survival. Survival (median 10.8 months) was not significantly prolonged by immediate WBRT. Salvage treatment was necessary in 87% of patients without immediate WBRT. All five scores identified groups of patients with superior prognosis. The recursive partitioning analysis (RPA) classes, the graded prognostic assessment (GPA) score and the score developed by Rades et al. identified a poor prognosis group, but the numbers of poor prognosis patients were very small. CONCLUSIONS: RPA and GPA appear to have the most utility in delineating exceptionally good or poor prognosis patients after resection of single brain metastasis, but this finding remains to be validated in a larger study population. Identification and validation of suitable prognostic scores hopefully will guide decision making regarding local treatment of solitary brain metastasis.

[How do Norwegian oncologists perceive their working conditions?]. / Hva mener norske onkologer om sin arbeidssituasjon?

BACKGROUND: After receiving worrying signals from its members concerning their workload, the Norwegian Oncology Society decided to review how Norwegian oncologists perceive their working conditions. MATERIAL AND METHODS: A questionnaire was sent to all doctors working in departments of oncology. They were asked to provide background information about themselves, how they experienced the working conditions, and what could be done to improve work satisfaction. Descriptive statistics were used for analysis of results. RESULTS: 174 of 298 doctors (58 %) answered the questionnaire. The median number of working hours per week was 52 hours for oncologists, and 45 hours for doctors in training. 72 % of oncologists and 56 % of doctors in training stated the workload is so high that it is difficult to complete all tasks. 63 % of oncologists felt that work was so energy-consuming that it affected their private life, 77 % of them were quite dissatisfied or very dissatisfied with time allocated to do research. 54 % of specialists and 72 % of doctors in training were very happy or happy with their job in general. 86 % of specialists and 61 % of doctors in training reported that more positions for oncologists and doctors in training, respectively, would increase their job satisfaction. INTERPRETATION: Doctors working in the field of oncology in Norway regard the workload to be too high. Oncologists believe that job satisfaction would improve if more time was allocated to research and if there were more positions for doctors at all levels.

Prognostic scores in brain metastases from breast cancer.

BACKGROUND: Prognostic scores might be useful tools both in clinical practice and clinical trials, where they can be used as stratification parameter. The available scores for patients with brain metastases have never been tested specifically in patients with primary breast cancer. It is therefore unknown which score is most appropriate for these patients. METHODS: Five previously published prognostic scores were evaluated in a group of 83 patients with brain metastases from breast cancer. All patients had been treated with whole-brain radiotherapy with or without radiosurgery or surgical resection. In addition, it was tested whether the parameters that form the basis of these scores actually have a prognostic impact in this biologically distinct group of brain metastases patients. RESULTS: The scores that performed best were the recursive partitioning analysis (RPA) classes and the score index for radiosurgery (SIR). However, disagreement between the parameters that form the basis of these scores and those that determine survival in the present group of patients and many reported data from the literature on brain metastases from breast cancer was found. With the four statistically significant prognostic factors identified here, a 3-tiered score can be created that performs slightly better than RPA and SIR. In addition, a 4-tiered score is also possible, which performs better than the three previous 4-tiered scores, incl. graded prognostic assessment (GPA) score and basic score for brain metastases (BSBM). CONCLUSION: A variety of prognostic models describe the survival of patients with brain metastases from breast cancer to a more or less satisfactory degree. However, the standard brain metastases scores might not fully appreciate the unique biology and time course of this disease, e.g., compared to lung cancer. It appears possible that inclusion of emerging prognostic factors will improve the results and allow for development and validation of a consensus score for broad clinical application. The model that is based on the authors own patient group, which is not large enough to fully evaluate a large number of potential prognostic factors, is meant to illustrate this point rather than to provide the definitive score.

Validation of the graded prognostic assessment index for patients with brain metastases.

BACKGROUND: The purpose of this study is to evaluate the performance of the new "Graded Prognostic Assessment" (GPA) index, which recently was developed from data in the Radiation Therapy Oncology Group (RTOG) database, in patients with brain metastases treated outside of randomized clinical trials. MATERIAL AND METHODS: The authors analyzed 232 patients with brain metastases and assigned these patients to the four indices previously evaluated by the RTOG (recursive partitioning analysis class, Score Index for Radiosurgery, Basic Score for Brain Metastases, and GPA). RESULTS: The present data confirm the results of the RTOG analysis. Each of the four indices splits the data set into prognostically different groups. In the GPA groups, median survival was 10.3, 5.6, 3.5, and 1.9 months, respectively (p<0.01). In the RTOG analysis, these figures were 11.0, 6.9, 3.8, and 2.6 months, respectively. CONCLUSION: These results confirm the validity of the GPA index in a patient population that most likely is more representative of the normal clinical situation than patients included in randomized trials.

Have changes in systemic treatment improved survival in patients with breast cancer metastatic to the brain?

Newly developed systemic treatment regimens might lead to improved survival also in the subgroup of breast cancer patients that harbour brain metastases. In order to examine this hypothesis, a matched pairs analysis was performed that involved one group of patients, which were treated after these new drugs were introduced, and one group of patients, which were treated approximately 10 years earlier. The two groups were well balanced for the known prognostic factors age, KPS, extracranial disease status, and recursive partitioning analysis class, as well as for the extent of brain treatment. The results show that the use of systemic chemotherapy has increased over time, both before and after the diagnosis of brain metastases. However, such treatment was performed nearly exclusively in those patients with brain metastases that belonged to the prognostically more favourable groups. Survival after whole-brain radiotherapy has remained unchanged in patients without further active treatment. It has improved in prognostically better patients and especially patients that received active treatment, where the 1-year survival rates have almost doubled. As these patient groups were small, confirmation of the results in other series should be attempted. Nevertheless, the present results are compatible with the hypothesis that improved systemic therapy might contribute to prolonged survival in patients with brain metastases from breast cancer.