How we treat octogenarians with brain metastases.

Biologically younger, fully independent octogenarians are able to tolerate most oncological treatments. Increasing frailty results in decreasing eligibility for certain treatments, e.g., chemotherapy and surgery. Most brain metastases are not an isolated problem, but part of widespread cancer dissemination, often in combination with compromised performance status. Multidisciplinary assessment is key in this vulnerable patient population where age, frailty, comorbidity and even moderate additional deficits from brain metastases or their treatment may result in immobilization, hospitalization, need for nursing home care, termination of systemic anticancer treatment etc. Here, we provide examples of successful treatment (surgery, radiosurgery, systemic therapy) and best supportive care, and comment on the limitations of prognostic scores, which often were developed in all-comers rather than octogenarians. Despite selection bias in retrospective studies, survival after radiosurgery was more encouraging than after whole-brain radiotherapy. Prospective research with focus on octogenarians is warranted to optimize outcomes.

Prospective randomized clinical studies involving reirradiation: update of a systematic review.

BACKGROUND: Reirradiation is a potentially useful option for many patients with recurrent cancer, aiming at cure or symptom palliation, depending on disease/recurrence type and stage. The purpose of this follow-up study to a previous review from 2016 was to summarize all recently published randomized trials. Points of interest again included identifcation of methodological strengths and weaknesses, practice-changing results, and open questions. MATERIAL AND METHODS: Systematic review of trials published between 2015 and February 2023. RESULTS: We reviewed 7 additional trials, most of which addressed reirradiation of head and neck or brain tumours. The median number of patients was 60. Mirroring the previous review, trial design, primary endpoints and statistical hypotheses varied widely. The updated results only impact on decision making for reirradiation of nasopharynx cancer and glioma. Patients with one of these diseases, as well as other head and neck cancers, may benefit from reirradiation-induced local control, e.g. in terms of progression-free survival. For the first time, hyperfractionated radiotherapy emerged as preferred option for recurrent, inoperable nasopharynx cancer. Despite better therapeutic ratio with hyperfractionation, serious toxicity remains a concern after high cumulative total doses. Randomized trials are still lacking for prostate cancer and other sites. CONCLUSION: Multicentric randomized trials on reirradiation are feasible and continue to refine the current standard of care for recurrent disease after previous radiotherapy. Ongoing prospective studies such as the European Society for Radiotherapy and Oncology and European Organisation for Research and Treatment of Cancer (ESTRO-EORTC) observational cohort ReCare (NCT: NCT03818503) will further shape the clinical practice of reirradiation.

Personalized radiotherapy of brain metastases: survival prediction by means of dichotomized or differentiated blood test results?

Background and objectives: The validated LabBM score (laboratory parameters in patients with brain metastases) represents a widely applicable survival prediction model, which incorporates 5 blood test results (serum lactate dehydrogenase (LDH), C-reactive protein (CRP), albumin, platelets and hemoglobin). All tests are classified as normal or abnormal, without accounting for the wide range of abnormality observed in practice. We tested the hypothesis that improved stratification might be possible, if more granular test results are employed. Methods: Retrospective analysis of 198 patients managed with primary whole-brain radiotherapy in one of the institutions who validated the original LabBM score. Results: For two blood tests (albumin, CRP), discrimination was best for the original dichotomized version (normal/abnormal). For two others (LDH, hemoglobin), a three-tiered classification was best. The number of patients with low platelet count was not large enough for detailed analyses. A modified LabBM score was developed, which separates the intermediate of originally 3 prognostic groups into 2 statistically significantly different strata, resulting in a 4-tiered score. Conclusion: This initial proof-of-principle study suggests that granular blood test results might contribute to further improvement of the score, or alternatively development of a nomogram, if additional large-scale studies confirm the encouraging results of the present analysis.

Diagnosis and Treatment of Peripheral and Cranial Nerve Tumors with Expert Recommendations: An EUropean Network for RAre CANcers (EURACAN) Initiative.

The 2021 WHO classification of the CNS Tumors identifies as "Peripheral nerve sheath tumors" (PNST) some entities with specific clinical and anatomical characteristics, histological and molecular markers, imaging findings, and aggressiveness. The Task Force has reviewed the evidence of diagnostic and therapeutic interventions, which is particularly low due to the rarity, and drawn recommendations accordingly. Tumor diagnosis is primarily based on hematoxylin and eosin-stained sections and immunohistochemistry. Molecular analysis is not essential to establish the histological nature of these tumors, although genetic analyses on DNA extracted from PNST (neurofibromas/schwannomas) is required to diagnose mosaic forms of NF1 and SPS. MRI is the gold-standard to delineate the extension with respect to adjacent structures. Gross-total resection is the first choice, and can be curative in benign lesions; however, the extent of resection must be balanced with preservation of nerve functioning. Radiotherapy can be omitted in benign tumors after complete resection and in NF-related tumors, due to the theoretic risk of secondary malignancies in a tumor-suppressor syndrome. Systemic therapy should be considered in incomplete resected plexiform neurofibromas/MPNSTs. MEK inhibitor selumetinib can be used in NF1 children ≥2 years with inoperable/symptomatic plexiform neurofibromas, while anthracycline-based treatment is the first choice for unresectable/locally advanced/metastatic MPNST. Clinical trials on other MEK1-2 inhibitors alone or in combination with mTOR inhibitors are under investigation in plexiform neurofibromas and MPNST, respectively.

Brain Metastases: Is There Still a Role for Whole-Brain Radiation Therapy?

Whole-brain radiation therapy (WBRT) has commonly been prescribed to palliate symptoms from brain metastases, to reduce the risk of local relapse after surgical resection, and to improve distant brain control after resection or radiosurgery. While targeting micrometastases throughout the brain can be considered advantageous, the simultaneous exposure of healthy brain tissue might cause adverse events. Attempts to mitigate the risk of neurocognitive decline after WBRT include the selective avoidance of the hippocampi, among others. Besides selective dose reduction, dose escalation to boost volumes, for example, simultaneous integrated boost, aiming at increased tumor control probability is technically feasible. While up-front radiotherapy for newly diagnosed brain metastases often employs radiosurgery or other techniques targeting visible lesions only, sequential (delayed) salvage treatment with WBRT might still become necessary. In addition, the presence of leptomeningeal tumors or very widespread parenchymatous brain metastases might prompt clinicians to prescribe early WBRT.

Personalized treatment of brain metastases: Evolving survival prediction models may benefit from evaluation of serum tumor markers (narrative review).

Treatment of a limited number of brain metastases (oligometastases) might include complex and sometimes invasive approaches, e.g. neurosurgical resection followed by post-operative stereotactic radiotherapy, and thus, correct identification of patients who are appropriate candidates is crucial. Both, staging procedures that visualize the true number of metastastic lesions and prognostic assessments that identify patients with limited survival, who should be managed with less complex, palliative approaches, are necessary before proceeding with local treatment that aims at eradication of all oligometastases. Some of the prognostic models, e.g. the LabBM score (laboratory parameters in patients with brain metastases), include blood biomarkers believed to represent surrogate markers of disease extent. In a recent study, patients with oligometastases and a LabBM score of 0 (no abnormal biomarkers) had an actuarial 5-year survival rate of 27% after neurosurgical resection and 39% after stereotactic radiotherapy. Other studies have tied serum tumor markers such as carcinoembryonic antigen (CEA) to survival outcomes. Even if head-to-head comparisons and large-scale definitive analyses are lacking, the available data suggest that attempts to integrate tumor marker levels in blood biomarker-based survival prediction models are warranted.

Critical impact of radiotherapy protocol compliance and quality in the treatment of retroperitoneal sarcomas: Results from the EORTC 62092-22092 STRASS trial.

BACKGROUND: The European Organization for Research and Treatment of Cancer 22092-62092 STRASS trial failed to demonstrate the superiority of neoadjuvant radiotherapy (RT) over surgery alone in patients with retroperitoneal sarcoma. Therefore, an RT quality-assurance program was added to the study protocol to detect and correct RT deviations. The authors report results from the trial RT quality-assurance program and its potential effect on patient outcomes. METHODS: To evaluate the effect of RT compliance on survival outcomes, a composite end point was created. It combined the information related to planning target volume coverage, target delineation, total dose received, and overall treatment time into 2 groups: non-RT-compliant (NRC) for patients who had unacceptable deviation(s) in any of the previous categories and RT-compliant (RC) otherwise. Abdominal recurrence-free survival (ARFS) and overall survival were compared between the 2 groups using a Cox proportional hazard model adjusted for known prognostic factors. RESULTS: Thirty-six of 125 patients (28.8%) were classified as NRC, and the remaining 89 patients (71.2%) were classified as RC. The 3-year ARFS rate was 66.8% (95% confidence interval [CI], 55.8%-75.7%) and 49.8% (95% CI, 32.7%-64.8%) for the RC and NRC groups, respectively (adjusted hazard ratio, 2.32; 95% CI, 1.25-4.32; P = .008). Local recurrence after macroscopic complete resection occurred in 13 of 89 patients (14.6%) versus 2 of 36 patients (5.6%) in the RC and NRC groups, respectively. CONCLUSIONS: The current analysis suggests a significant benefit in terms of ARFS in favor of the RC group. This association did not translate into less local relapses after complete resection in the RC group. Multidisciplinary collaboration and review of cases are critical to avoid geographic misses, especially for rare tumors like retroperitoneal sarcoma.

Evolution of treatment strategies for oligometastatic NSCLC patients - A systematic review of the literature.

BACKGROUND: The concept of oligometastatic disease (OMD) has expanded the scope of potentially curative therapy for metastatic NSCLC. However, large uncertainties remain regarding its definition and optimal management strategies. We therefore conducted a systematic review to investigate the value of various multimodality treatment concepts. METHODS: We searched the available literature in Pubmed, Medline and EMBASE using the terms "oligomet*", "synchron*", "oligorec*", "metachr*" "NSCLC", "lung cancer" and "stage IV" and included studies reporting treatment regimens and outcomes on radically treated patients with either "synchronous", "metachronous" or "mixed" OMD. Only de-novo diagnosis of OMD was considered. The impact of patient and treatment characteristics on overall survival (OS) and time trends in patterns of care were investigated. RESULTS: 54 studies published between 1987 and 2018 were included. Despite a wide range of OMD definitions, 90.1% of patients were treated for a single metastasis. Systemic therapy was used as backbone treatment for most patients. Although surgery was the preferred local treatment in earlier studies, the use of stereotactic radiotherapy increased rapidly after 2011. No OS difference was observed between surgery or radiotherapy as the treatment of primary tumor or metastases, respectively. A time trend towards improved OS after 2011 could be detected. CONCLUSIONS: While evidence in favor of radical treatment is emerging, most studies remain retrospective and mainly evaluate patients with singular metastases. While surgery, stereotactic radiotherapy and chemotherapy are the cornerstones of current treatment strategies, future clinical trials need to address the high risk of distant metastases by integrating targeted or immunotherapy.

Re-irradiation for Recurrent Primary Brain Tumors.

BACKGROUND: Historically, radiation oncologists have been cautious about re-irradiating brain tumors because of concerns about the risks of late central nervous system (CNS) toxicity, especially radionecrosis, that may occur several months to years following treatment. Today there are still limited prospective data addressing this approach. MATERIALS AND METHODS: Systematic review of published trials reporting clinical results after re-irradiation of patients with different types of brain tumors was performed. RESULTS: Data mainly related to glioblastoma, anaplastic glioma, medulloblastoma, ependymoma and meningioma have been published. Randomized studies are scarce. As in first-line scenarios, efficacy of radiotherapy is influenced by histology. Based on the reported outcomes, preliminary recommendations for dose/fractionation regimens can be given. CONCLUSION: Re-irradiation of brain tumors is increasingly considered as our understanding of brain tolerance to radiation evolves and developments in radiation technology and imaging make highly accurate targeting of recurrent tumors possible. With developments in systemic therapy, further exploration of the role of re-irradiation on its own or in combination with novel agents is needed.

Scientific impact of studies published in temporarily available radiation oncology journals: a citation analysis.

The purpose of this study was to review all articles published in two temporarily available radiation oncology journals (Radiation Oncology Investigations, Journal of Radiosurgery) in order to evaluate their scientific impact. From several potential measures of impact and relevance of research, we selected article citation rate because landmark or practice-changing research is likely to be cited frequently. The citation database Scopus was used to analyse number of citations. During the time period 1996-1999 the journal Radiation Oncology Investigations published 205 articles, which achieved a median number of 6 citations (range 0-116). However, the most frequently cited article in the first 4 volumes achieved only 23 citations. The Journal of Radiosurgery published only 31 articles, all in the year 1999, which achieved a median number of 1 citation (range 0-11). No prospective randomized studies or phase I-II collaborative group trials were published in these journals. Apparently, the Journal of Radiosurgery acquired relatively few manuscripts that were interesting and important enough to impact clinical practice. Radiation Oncology Investigations' citation pattern was better and closer related to that reported in several previous studies focusing on the field of radiation oncology. The vast majority of articles published in temporarily available radiation oncology journals had limited clinical impact and achieved few citations. Highly influential research was unlikely to be submitted during the initial phase of establishing new radiation oncology journals.

Normal tissue studies in radiation oncology: A systematic review of highly cited articles and citation patterns.

Radiation therapy is one of the cornerstones of modern multidisciplinary cancer treatment. Normal tissue tolerance is critical as radiation-induced side effects may compromise organ function and quality of life. The importance of normal tissue research is reflected by the large number of scientific articles, which have been published between 2006 and 2010. The present study identified important areas of research as well as seminal publications. The article citation rate is among the potential indicators of scientific impact. Highly cited articles, arbitrarily defined as those with ≥15 citations, were identified via a systematic search of the citation database, Scopus. Up to 608 articles per year were published between 2006 and 2010, however, <10% of publications in each year accumulated ≥15 citations. This figure is notably low, when compared with other oncology studies. A large variety of preclinical and clinical topics, including toxicity prediction, the dose-volume relationship and radioprotectors, accumulated ≥15 citations. However, clinical prevention or mitigation studies were underrepresented. The following conclusion may be drawn from the present study; despite the improved technology that has resulted in superior dose distribution, clinical prevention or mitigation studies are critical and must receive higher priority, funding and attention.

Combined radio- and chemotherapy for non-small cell lung cancer: systematic review of landmark studies based on acquired citations.

The important role of combined chemoradiation for several groups of patients with non-small cell lung cancer (NSCLC) is reflected by the large number of scientific articles published during the last 30 years. Different measures of impact and clinical relevance of published research are available, each with its own pros and cons. For this review, article citation rate was chosen. Highly cited articles were identified through systematic search of the citation database Scopus. Among the 100 most often cited articles, meta-analyses (n = 5) achieved a median of 203 citations, guidelines (n = 7) 97, phase III trials (n = 29) 168, phase II trials (n = 21) 135, phase I trials (n = 7) 88, and others combined 115.5 (p = 0.001). Numerous national and international cooperative groups and several single institutions were actively involved in performing often cited, high-impact trials, reflecting the fact that NSCLC is a world-wide challenge that requires research collaboration. Platinum-containing combinations have evolved into a standard of care, typically administered concurrently. The issue of radiotherapy fractionation and total dose has also been studied extensively, yet with less conclusive results. Differences in target volume definition have been addressed. However, it was not possible to test all theoretically possible combinations of radiotherapy regimens, drugs, and drug doses (lower radiosensitizing doses compared to higher systemically active doses). That is why current guidelines offer physicians a choice of different, presumably equivalent treatment alternatives. This review identifies open questions and strategies for further research.

Increasing frequency of reirradiation studies in radiation oncology: systematic review of highly cited articles.

OBJECTIVES: Identification of the most influential scientific publications and directions of mainstream reirradiation research. METHODS: A systematic search of the database Scopus (Elsevier B.V., www.scopus.com) was performed, which focused on the time period 1998-2010. Patterns of citation were analysed (total number of citations accumulated independently of their origin and proportion of highly cited articles, arbitrarily defined as those with ≥50 citations). RESULTS: Up to 64 articles were published each year. Numbers increased over time, especially after the year 2007. Among all 76 articles with at least 50 citations, 28 (37%) focused on head and neck cancer, 27 (36%) on brain tumours including metastases, and 5 (7%) on bone metastases. Most articles evaluated external beam approaches while 10 (13%) focused on brachytherapy. Many of the often quoted publications reported on stereotactic and/or intensity-modulated radiotherapy. Two (3%) reported on randomised clinical studies and 10 (13%) on non-randomised prospective clinical studies (single institution or cooperative group). Only two articles (3%) reported on experimental animal studies. CONCLUSIONS: The number of published reirradiation studies has increased in recent years. Many studies examined highly conformal and precise radiotherapy, in particular of brain and head and neck tumours. Given that few randomised clinical trials were published, efforts to increase this type of research activity are warranted.

Diagnosis-specific graded prognostic assessment score is valid in patients with brain metastases treated in routine clinical practice in two European countries.

BACKGROUND: Assessment of cancer- and host-related prognostic factors has a long tradition in patients with brain metastases. In continuation of large-scale studies performed by the Radiation Therapy Oncology Group (RTOG) in the United States, the 4-tiered diagnosis-specific graded prognostic assessment (DS-GPA) score has been developed. It stratifies patients with common primary tumours metastasizing to the brain (malignant melanoma, lung, breast, kidney and gastrointestinal cancers) into subgroups with different prognoses. However, many patients in the DS-GPA study were treated with surgical resection or radiosurgery (SRS). The present multi-institutional analysis examined for the first time whether DS-GPA is a valid score in European patients managed in routine clinical practice. MATERIAL/METHODS: This was a retrospective analysis of 412 patients with primary malignant melanoma, lung, breast, kidney or gastrointestinal cancers. Survival was evaluated in uni- and multivariate tests. RESULTS: DS-GPA significantly predicted survival and outperformed initial GPA, a score that is not diagnosis-specific. Median survival by DS-GPA strata (all 412 patients) was 2.7, 3.6, 7.0 and 11.3 months in the 4 groups with 0-1, 1.5-2, 2.5-3 and 3.5-4 points, respectively. The previously published survival data (median 7.2 months for all patients) could not be replicated in this cohort (median 3.6 months). CONCLUSIONS: DS-GPA is a valid prognostic score that might improve shared decision making as well as patient stratification in prospective clinical trials.

Brain metastases in patients under 50 years of age: retrospective analysis.

Several previous publications suggested that younger patients with brain metastases have longer survival than older patients. However, detailed studies of younger patient groups are scarce. Therefore, a multi-institutional analysis of younger patients with brain metastases was performed (defined as adults with age <50 years). Prognostic factors for survival were examined by uni- and multivariate analyses and compared to those obtained in patients with age ≥50 years. Multivariate analysis of 106 patients (median age 44 years, range 23-49 years) revealed three independent prognostic factors for survival: performance status, extracranial metastases and primary tumor control. Survival was significantly better in patients treated after the year 2000 (median 9.4 months) as compared to those treated before the year 2000 (median 5.1 months, p = 0.04). This improvement appeared to be related to an increased use of surgery or radiosurgery (SRS) and decreasing numbers of patients with uncontrolled primary tumor. Irrespective of management approach, survival beyond 5 years was uncommon (actuarial rate 6 %; 17 % in patients treated with upfront surgery or SRS). In conclusion, more intense multidisciplinary approaches aiming at control both in the brain, extracranial metastatic sites, and primary tumor site might have contributed to gradual survival improvements in recent years. Nevertheless, further efforts are necessary to improve long-term survival.

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.

Prognostic scores in patients with brain metastases from non-small cell lung cancer.

INTRODUCTION: Prognostic scores might be useful tools in both clinical practice and clinical trials, where they can be used as stratification parameter. The five available scores for the general population of patients with brain metastases have never been tested specifically in patients with non-small cell lung cancer (NSCLC). No comparison to the two NSCLC-specific scores has been made either. Hence, it remains unclear which score is most appropriate for these patients. METHODS: We evaluated seven previously published prognostic scores in a group of 183 patients with brain metastases from NSCLC. All patients had been treated outside of clinical studies with whole brain radiotherapy with or without radiosurgery or surgical resection. RESULTS: The three scores with significant prognostic impact were the recursive partitioning analysis classes, the basic score for brain metastases, and the graded prognostic assessment (GPA) score. All three score systems were developed in a general population of patients with brain metastases. The GPA score performed better than the others. In this four-tiered system, the 1-year survival was 43, 20, 8, and 0%, respectively. CONCLUSION: Three prognostic scoring models describe the survival of patients with brain metastases from NSCLC to a satisfactory degree. In the current patient population, GPA performs better than the others. The two NSCLC-specific scores were developed in radiosurgery-treated populations, and their prognostic impact in a general NSCLC population seems limited.

Disease presentation and outcome in very young patients with brain metastases from breast cancer.

AIMS AND BACKGROUND: Little information is available on disease presentation and treatment outcome in very young patients with brain metastases from breast cancer. Therefore, we evaluated our results in this group. METHODS: In our database, 7/74 breast cancer patients treated for brain metastases were < 40 years old. All received whole-brain radiation therapy plus individual local or systemic measures. RESULTS: In patients with information available, tumors were poorly differentiated and metastatic to the axillary lymph nodes at primary diagnosis. All patients had extracranial metastases. Two died from their brain disease within 5 months. Five patients died from extracranial progression after 3-84 months (2 long-term survivors beyond 2 years, characterized by single brain lesions and high performance status). CONCLUSIONS: Very young patients did not achieve a better outcome than intermediate age groups. Whole-brain radiation therapy plus surgery or radiosurgery provided durable CNS control in most of the patients. Improved systemic therapy appears to represent the key to a better outcome.

Can prophylactic breast irradiation contribute to cardiac toxicity in patients with prostate cancer receiving androgen suppressing drugs?

BACKGROUND: Androgen suppression treatment (AST) might increase the risk of cardiac morbidity in prostate cancer patients. Possible explanations were provided, however, they disregard the potential contribution of prophylactic radiotherapy to the mamillary regions (PMRT, prescribed to avoid gynecomastia). METHODS: We studied the exposure of the heart in a typical electron beam PMRT setting by evaluating computed tomography (CT) scans in 40 non-cancer patients (age 65 and 75 years in 50% each) and 17 prostate cancer patients. Five of the younger, 7 of the older and 4 of the cancer patients had significant cardiac disease. RESULTS: The median distance between skin and outer heart contour decreased with age. In all three groups, patients with cardiac morbidity had smaller distances. When using the CT-determined PMRT beam energy, 10% of the younger, 15% of the older and none of the prostate cancer patients would receive approximately 50% of the prescription dose to a part of the heart (2 had no history of cardiac disease). When using the clinically rather than CT-determined beam energy, as often done in daily practice, an additional 12.5% of the non-cancer and 12% of the prostate cancer patients would be exposed to comparably high doses. CONCLUSION: The present data provide preliminary evidence that PMRT might be a factor that contributes to cardiac side effects. Previous studies that established a relationship between AST and cardiac morbidity did not include information on delivery of PMRT.