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Current Oncology Reports Aug 2022To review state of art and relevant advances in the molecular genetics and management of ependymomas of children and adults. (Review)
Review
PURPOSE OF REVIEW
To review state of art and relevant advances in the molecular genetics and management of ependymomas of children and adults.
RECENT FINDINGS
Ependymomas may occur either in the brain or in the spinal cord. Compared with intracranial ependymomas, spinal ependymomas are less frequent and exhibit a better prognosis. The new WHO classification of CNS tumors of 2021 has subdivided ependymomas into different histomolecular subgroups with different outcome. The majority of studies have shown a major impact of extent of resection; thus, a complete resection must be performed, whenever possible, at first surgery or at reoperation. Conformal radiotherapy is recommended for grade 3 or incompletely resected grade II tumors. Proton therapy is increasingly employed especially in children to reduce the risk of neurocognitive and endocrine sequelae. Craniospinal irradiation is reserved for metastatic disease. Chemotherapy is not useful as primary treatment and is commonly employed as salvage treatment for patients failing surgery and radiotherapy. Standard treatments are still the mainstay of treatment: the discovery of new druggable pathways will hopefully increase the therapeutic armamentarium in the near future.
Topics: Adult; Brain Neoplasms; Child; Ependymoma; Humans; Prognosis; Salvage Therapy
PubMed: 35384591
DOI: 10.1007/s11912-022-01260-w -
Journal of Clinical Oncology : Official... Nov 2022Photon involved-field radiotherapy (IFRT) is the standard-of-care radiotherapy for patients with leptomeningeal metastasis (LM) from solid tumors. We tested whether... (Randomized Controlled Trial)
Randomized Controlled Trial
PURPOSE
Photon involved-field radiotherapy (IFRT) is the standard-of-care radiotherapy for patients with leptomeningeal metastasis (LM) from solid tumors. We tested whether proton craniospinal irradiation (pCSI) encompassing the entire CNS would result in superior CNS progression-free survival (PFS) compared with IFRT.
PATIENTS AND METHODS
We conducted a randomized, phase II trial of pCSI versus IFRT in patients with non-small-cell lung cancer and breast cancers with LM. We enrolled patients with other solid tumors to an exploratory pCSI group. For the randomized groups, patients were assigned (2:1), stratified by histology and systemic disease status, to pCSI or IFRT. The primary end point was CNS PFS. Secondary end points included overall survival (OS) and treatment-related adverse events (TAEs).
RESULTS
Between April 16, 2020, and October 11, 2021, 42 and 21 patients were randomly assigned to pCSI and IFRT, respectively. At planned interim analysis, a significant benefit in CNS PFS was observed with pCSI (median 7.5 months; 95% CI, 6.6 months to not reached) compared with IFRT (2.3 months; 95% CI, 1.2 to 5.8 months; < .001). We also observed OS benefit with pCSI (9.9 months; 95% CI, 7.5 months to not reached) versus IFRT (6.0 months; 95% CI, 3.9 months to not reached; = .029). There was no difference in the rate of grade 3 and 4 TAEs ( = .19). In the exploratory pCSI group, 35 patients enrolled, the median CNS PFS was 5.8 months (95% CI, 4.4 to 9.1 months) and OS was 6.6 months (95% CI, 5.4 to 11 months).
CONCLUSION
Compared with photon IFRT, we found pCSI improved CNS PFS and OS for patients with non-small-cell lung cancer and breast cancer with LM with no increase in serious TAEs.
Topics: Humans; Carcinoma, Non-Small-Cell Lung; Protons; Craniospinal Irradiation; Lung Neoplasms; Proton Therapy; Meningeal Carcinomatosis; Antineoplastic Combined Chemotherapy Protocols
PubMed: 35802849
DOI: 10.1200/JCO.22.01148 -
Neuro-oncology Apr 2022The incidence of intracranial germ cell tumors (iGCT) is much lower in European and North American (E&NA) than in Asian population. However, E&NA cooperative groups have...
The incidence of intracranial germ cell tumors (iGCT) is much lower in European and North American (E&NA) than in Asian population. However, E&NA cooperative groups have simultaneously developed with success treatment strategies with specific attention paid to long-term sequelae. Neurological sequelae may be reduced by establishing a diagnosis with an endoscopic biopsy and/or cerebrospinal fluid (CSF) and/or serum analysis, deferring the need to perform a radical surgery. Depending on markers and/or histological characteristics, patients are treated as either germinoma or non-germinomatous germ cell tumors (NGGCT). Metastatic disease is defined by a positive CSF cytology and/or distant drops in craniospinal MRI. The combination of surgery and/or chemotherapy and radiation therapy is tailored according to grouping and staging. With more than 90% 5-year event-free survival (EFS), localized germinomas can be managed without aggressive surgery, and benefit from chemotherapy followed by whole ventricular irradiation with local boost. Bifocal germinomas are treated as non-metastatic entities. Metastatic germinomas may be cured with craniospinal irradiation. With a 5-year EFS over 70%, NGGCT benefit from chemotherapy followed by delayed surgery in case of residual disease, and some form of radiotherapy. Future strategies will aim at decreasing long-term side effects while preserving high cure rates.
Topics: Adolescent; Brain Neoplasms; Consensus; Germinoma; Humans; Male; Neoplasms, Germ Cell and Embryonal; Retrospective Studies; Testicular Neoplasms; Young Adult
PubMed: 34724065
DOI: 10.1093/neuonc/noab252 -
The Lancet. Oncology Jul 2017International consensus recognises four medulloblastoma molecular subgroups: WNT (MB), SHH (MB), group 3 (MB), and group 4 (MB), each defined by their characteristic...
BACKGROUND
International consensus recognises four medulloblastoma molecular subgroups: WNT (MB), SHH (MB), group 3 (MB), and group 4 (MB), each defined by their characteristic genome-wide transcriptomic and DNA methylomic profiles. These subgroups have distinct clinicopathological and molecular features, and underpin current disease subclassification and initial subgroup-directed therapies that are underway in clinical trials. However, substantial biological heterogeneity and differences in survival are apparent within each subgroup, which remain to be resolved. We aimed to investigate whether additional molecular subgroups exist within childhood medulloblastoma and whether these could be used to improve disease subclassification and prognosis predictions.
METHODS
In this retrospective cohort study, we assessed 428 primary medulloblastoma samples collected from UK Children's Cancer and Leukaemia Group (CCLG) treatment centres (UK), collaborating European institutions, and the UKCCSG-SIOP-PNET3 European clinical trial. An independent validation cohort (n=276) of archival tumour samples was also analysed. We analysed samples from patients with childhood medulloblastoma who were aged 0-16 years at diagnosis, and had central review of pathology and comprehensive clinical data. We did comprehensive molecular profiling, including DNA methylation microarray analysis, and did unsupervised class discovery of test and validation cohorts to identify consensus primary molecular subgroups and characterise their clinical and biological significance. We modelled survival of patients aged 3-16 years in patients (n=215) who had craniospinal irradiation and had been treated with a curative intent.
FINDINGS
Seven robust and reproducible primary molecular subgroups of childhood medulloblastoma were identified. MB remained unchanged and each remaining consensus subgroup was split in two. MB was split into age-dependent subgroups corresponding to infant (<4·3 years; MB; n=65) and childhood patients (≥4·3 years; MB; n=38). MB and MB were each split into high-risk (MB [n=65] and MB [n=85]) and low-risk (MB [n=50] and MB [n=73]) subgroups. These biological subgroups were validated in the independent cohort. We identified features of the seven subgroups that were predictive of outcome. Cross-validated subgroup-dependent survival models, incorporating these novel subgroups along with secondary clinicopathological and molecular features and established disease risk-factors, outperformed existing disease risk-stratification schemes. These subgroup-dependent models stratified patients into four clinical risk groups for 5-year progression-free survival: favourable risk (54 [25%] of 215 patients; 91% survival [95% CI 82-100]); standard risk (50 [23%] patients; 81% survival [70-94]); high-risk (82 [38%] patients; 42% survival [31-56]); and very high-risk (29 [13%] patients; 28% survival [14-56]).
INTERPRETATION
The discovery of seven novel, clinically significant subgroups improves disease risk-stratification and could inform treatment decisions. These data provide a new foundation for future research and clinical investigations.
FUNDING
Cancer Research UK, The Tom Grahame Trust, Star for Harris, Action Medical Research, SPARKS, The JGW Patterson Foundation, The INSTINCT network (co-funded by The Brain Tumour Charity, Great Ormond Street Children's Charity, and Children with Cancer UK).
Topics: Adolescent; Age Factors; Cerebellar Neoplasms; Child; Child, Preschool; DNA Methylation; Disease-Free Survival; Female; Gene Amplification; Humans; Infant; Infant, Newborn; Kruppel-Like Transcription Factors; Male; Medulloblastoma; Mutation; N-Myc Proto-Oncogene Protein; Nuclear Proteins; Patched-1 Receptor; Proto-Oncogene Proteins c-myc; Repressor Proteins; Retrospective Studies; Risk Assessment; Risk Factors; Smoothened Receptor; Survival Rate; Telomerase; Transcriptome; Tumor Suppressor Protein p53; Zinc Finger Protein Gli2; beta Catenin
PubMed: 28545823
DOI: 10.1016/S1470-2045(17)30243-7 -
Reports of Practical Oncology and... 2019To explore available recent literature related to cardiotoxicity following mediastinal radiation. (Review)
Review
AIM
To explore available recent literature related to cardiotoxicity following mediastinal radiation.
BACKGROUND
Radiotherapy-related heart injury is well documented, with no apparent safety threshold dose. The number of long-term cancer survivors exposed to mediastinal radiotherapy at some point of their treatment is increasing. Heart dosimetric parameters are of great importance in developing a treatment plan, but few data are available regarding radiosensitivity and dose-volume constraints for specific heart structures.
MATERIALS AND METHODS
In October 2018, we identified articles published after 1990 through a PubMed/MEDLINE database search. The authors examined rough search results and manuscripts not relevant for the topic were excluded. We extracted clinical outcomes following mediastinal radiotherapy of childhood cancers, lymphoma, medulloblastoma, thymic cancers and hematopoietic cell transplantation survivors and evaluated treatment planning data, whenever available.
RESULTS
A total of 1311 manuscripts were identified in our first-round search. Of these manuscripts, only 115 articles, matching our selection criteria, were included.
CONCLUSIONS
Studies uniformly show a linear radiation dose-response relationship between mean absorbed dose to the heart (heart-D) and the risk of dying as a result of cardiac disease, particularly when heart-D exceeds 5 Gy. Limited data are available regarding dose-volume predictors for heart substructures and the risk of subsequent cardiac toxicity. An individual patient's cardiotoxicity risk can be modified with advanced treatment planning techniques, including deep inspiration breath hold. Proton therapy is currently showing advantages in improving treatment planning parameters when compared to advanced photon techniques in lymphoma, thymic malignancies, malignant mesothelioma and craniospinal irradiation.
PubMed: 31719801
DOI: 10.1016/j.rpor.2019.09.002 -
Clinical and Translational Radiation... Jan 2023Tomotherapy is a method of delivering rotational IMRT offering various advantages, notably for complex and large targets such as the cranio-spinal axis. This systematic... (Review)
Review
Tomotherapy is a method of delivering rotational IMRT offering various advantages, notably for complex and large targets such as the cranio-spinal axis. This systematic literature review reports on main clinical outcomes and toxicities in patients with various cancer types that received whole craniospinal axis irradiation (CSI) using Tomotherapy and offers a comprehensive comparison between Tomotherapy and other radiotherapy delivery techniques. Databases including PubMed, PubMed Central, Embase, and Cochrane were searched using the keywords "tomotherapy" AND "craniospinal". Fifty-six papers were included in the review. Patient population was adult in 9 papers, paediatric in 26 papers and mixed in 14 papers. Patients treated with helical Tomotherapy had similar disease-specific clinical outcomes and toxicities as patients treated using other techniques. Compared to any other technique, Tomotherapy provides better target coverage, homogeneity, and conformity in 23, 34 and 22 reports. Tomotherapy showed better organ-at-risk sparing for the thyroid, parotids, cochlea, eyes, heart and esophagus. Beam-On-Time (BOT) was reported to be longer for Tomotherapy in most studies (Median BOT: HT = 11 min, VMAT = 5.49 min, 3DCRT = 1.46 min). In conclusion, Tomotherapy offers good cranio-spinal axis coverage with improved homogeneity and conformity compared to other techniques, but with a considerably longer treatment time. Clinical outcome and toxicities suggest using Tomotherapy for CSI is efficient and safe.
PubMed: 36407491
DOI: 10.1016/j.ctro.2022.11.003 -
Acta Neuropathologica Oct 2022Methylation profiling has radically transformed our understanding of tumors previously called central nervous system primitive neuro-ectodermal tumors (CNS-PNET). While... (Clinical Trial)
Clinical Trial
Molecular classification and outcome of children with rare CNS embryonal tumors: results from St. Jude Children's Research Hospital including the multi-center SJYC07 and SJMB03 clinical trials.
Methylation profiling has radically transformed our understanding of tumors previously called central nervous system primitive neuro-ectodermal tumors (CNS-PNET). While this marks a momentous step toward defining key differences, reclassification has thrown treatment into disarray. To shed light on response to therapy and guide clinical decision-making, we report outcomes and molecular features of children with CNS-PNETs from two multi-center risk-adapted studies (SJMB03 for patients ≥ 3 years; SJYC07 for patients < 3 years) complemented by a non-protocol institutional cohort. Seventy patients who had a histological diagnosis of CNS-PNET or CNS embryonal tumor from one of the new categories that has supplanted CNS-PNET were included. This cohort was molecularly characterized by DNA methylation profiling (n = 70), whole-exome sequencing (n = 53), RNA sequencing (n = 20), and germline sequencing (n = 28). Clinical characteristics were detailed, and treatment was divided into craniospinal irradiation (CSI)-containing (SJMB03 and SJMB03-like) and CSI-sparing therapy (SJYC07 and SJYC07-like). When the cohort was analyzed in its entirety, no differences were observed in the 5-year survival rates even when CSI-containing therapy was compared to CSI-sparing therapy. However, when analyzed by DNA methylation molecular grouping, significant survival differences were observed, and treatment particulars provided suggestions of therapeutic response. Patients with CNS neuroblastoma with FOXR2 activation (CNS-NB-FOXR2) had a 5-year event-free survival (EFS)/overall survival (OS) of 66.7% ± 19.2%/83.3% ± 15.2%, and CIC rearranged sarcoma (CNS-SARC-CIC) had a 5-year EFS/OS both of 57.1% ± 18.7% with most receiving regimens that contained radiation (focal or CSI) and multidrug chemotherapy. Patients with high-grade neuroepithelial tumor with BCOR alteration (HGNET-BCOR) had abysmal responses to upfront chemotherapy-only regimens (5-year EFS = 0%), but survival extended with salvage radiation after progression [5-year OS = 53.6% ± 20.1%]. Patients with embryonal tumor with multilayered rosettes (ETMR) or high-grade glioma/glioblastoma multiforme (HGG/GBM) did not respond favorably to any modality (5-year EFS/OS = 10.7 ± 5.8%/17.9 ± 7.2%, and 10% ± 9.0%/10% ± 9.0%, respectively). As an accompaniment, we have assembled this data onto an interactive website to allow users to probe and query the cases. By reporting on a carefully matched clinical and molecular cohort, we provide the needed insight for future clinical management.
Topics: Brain Neoplasms; Central Nervous System Neoplasms; Child; Forkhead Transcription Factors; Glioblastoma; Hospitals; Humans; Neoplasms, Germ Cell and Embryonal; Neuroectodermal Tumors, Primitive
PubMed: 35982322
DOI: 10.1007/s00401-022-02484-7 -
Cancers Jan 2020Medulloblastoma is an embryonal tumor that shows a predilection for distant metastatic spread and leptomeningeal seeding. For most patients, optimal management of... (Review)
Review
Medulloblastoma is an embryonal tumor that shows a predilection for distant metastatic spread and leptomeningeal seeding. For most patients, optimal management of medulloblastoma includes maximum safe resection followed by adjuvant craniospinal irradiation (CSI) and chemotherapy. Although CSI is crucial in treating medulloblastoma, the realization that medulloblastoma is a heterogeneous disease comprising four distinct molecular subgroups (wingless [WNT], sonic hedgehog [SHH], Group 3 [G3], and Group 4 [G4]) with distinct clinical characteristics and prognoses has refocused efforts to better define the optimal role of CSI within and across disease subgroups. The ability to deliver clinically relevant CSI to preclinical models of medulloblastoma offers the potential to study radiation dose and volume effects on tumor control and toxicity in these subgroups and to identify subgroup-specific combination adjuvant therapies. Recent efforts have employed commercial image-guided small animal irradiation systems as well as custom approaches to deliver accurate and reproducible fractionated CSI in various preclinical models of medulloblastoma. Here, we provide an overview of the current clinical indications for, and technical aspects of, irradiation of pediatric medulloblastoma. We then review the current literature on preclinical modeling of and treatment interventions for medulloblastoma and conclude with a summary of challenges in the field of preclinical modeling of CSI for the treatment of leptomeningeal seeding tumors.
PubMed: 31948065
DOI: 10.3390/cancers12010133 -
Neurologia Medico-chirurgica Nov 2016Medulloblastoma (MB) is one of the most frequent malignant brain tumors in children. The current standard treatment regimen consists of surgical resection, craniospinal... (Review)
Review
Medulloblastoma (MB) is one of the most frequent malignant brain tumors in children. The current standard treatment regimen consists of surgical resection, craniospinal irradiation, and adjuvant chemotherapy. Although these treatments have the potential to increase the survival of 70-80% of patients with MB, they are also associated with serious treatment-induced morbidity. The current risk stratification of MB is based on clinical factors, including age at presentation, metastatic status, and the presence of residual tumor following resection. In addition, recent genomic studies indicate that MB consists of at least four distinct molecular subgroups: WNT, sonic hedgehog (SHH), Group 3, and Group 4. WNT and SHH MBs are characterized by aberrations in the WNT and SHH signaling pathways, respectively. WNT MB has the best prognosis compared to the other MBs, while SHH MB has an intermediate prognosis. The underlying signaling pathways associated with Group 3 and 4 MBs have not been identified. Group 3 MB is frequently associated with metastasis, resulting in a poor prognosis, while Group 4 is sometimes associated with metastasis and has an intermediate prognosis. Group 4 is the most frequent MB and represents 35% of all MBs. These findings suggest that MB is a heterogeneous disease, and that MB subgroups have distinct molecular, demographic, and clinical characteristics. The molecular classification of MBs is redefining the risk stratification of patients with MB, and has the potential to identify new therapeutic strategies for the treatment of MB.
Topics: Cerebellar Neoplasms; Gene Expression Profiling; Humans; Medulloblastoma
PubMed: 27238212
DOI: 10.2176/nmc.ra.2016-0016 -
Craniospinal Irradiation: A Dosimetric Comparison Between O-Ring Linac and Conventional C-arm Linac.Advances in Radiation Oncology 2023The aim of this study was to perform a dosimetric evaluation between craniospinal irradiation volumetric modulated arc therapy plans designed for an O-Ring and a...
PURPOSE
The aim of this study was to perform a dosimetric evaluation between craniospinal irradiation volumetric modulated arc therapy plans designed for an O-Ring and a conventional C-arm Linac.
METHODS AND MATERIALS
Two adult patients were selected for this study. Two plans were designed one for a TrueBeam Edge and one for Halcyon O-ring Linac for each patient. The evaluation of the plans was conducted in terms of dose volume histogram analysis of the target volume and organs at risk (OARs) along with total plan monitor units and beam-on time. Paired sample test was performed to compare D and D of OARs for each plan's comparison. The delivery of volumetric modulated arc therapy plans was evaluated using Octavius 4D phantom.
RESULTS
All plans demonstrated dose distributions with sufficient planned target volume conformity and homogeneity. The Homogeneity Index and Conformity Index for all plans were found comparable. The paired sample test did not demonstrate significant difference in terms of D and D of OARs between plans for both patients. All plans met the threshold of 90%, with Halcyon plans having higher gamma passing rates.
CONCLUSIONS
Craniospinal irradiation plans generated for Halcyon and Edge are equivalent in terms of plan quality and dose sparing at OARs. The small variations may have originated from the differences in beam profile or mean energy, the degree of the modulation for each plan and characteristics of multi leaf collimators for each treatment unit. Halcyon is able to deliver a distinctly faster treatment, but Edge provides an automatic rotational correction for patient positioning.
PubMed: 36636383
DOI: 10.1016/j.adro.2022.101139