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Background:
The current standard of care for newly diagnosed glioblastoma (GBM) is surgical resection, followed by radiation therapy (RT) with concurrent and adjuvant temozolomide chemotherapy (TMZ-CHT).. The patients outcome is still poor. In this study we evaluated hypofractionated radiation therapy (HFRT), instead of standard fractionated radia...
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Citations
... On the clinical side, new hypo-fractionated clinical protocols were progressively introduced for different pathologies and body regions allowing access to effective and generally more advanced and comfortable therapies for a greater and greater number of patients [4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20][21]. ...
Background:
Hypo-fractionation can be an effective strategy to lower costs and save time, increasing patient access to advanced radiation therapy. To demonstrate this potential in practice within the context of temporal evolution, a twenty-year analysis of a representative radiation therapy facility from 2003 to 2022 was conducted. This analysis utilized comprehensive data to quantitatively evaluate the connections between advanced clinical protocols and technological improvements. The findings provide valuable insights to the management team, helping them ensure the delivery of high-quality treatments in a sustainable manner.
Methods:
Several parameters related to treatment technique, patient positioning, dose prescription, fractionation, equipment technology content, machine workload and throughput, therapy times and patients access counts were extracted from departmental database and analyzed on a yearly basis by means of linear regression.
Results:
Patients increased by 121 ± 6 new per year (NPY). Since 2010, the incidence of hypo-fractionation protocols grew thanks to increasing Linac technology. In seven years, both the average number of fractions and daily machine workload decreased by -0.84 ± 0.12 fractions/year and -1.61 ± 0.35 patients/year, respectively. The implementation of advanced dose delivery techniques, image guidance and high dose rate beams for high fraction doses, currently systematically used, has increased the complexity and reduced daily treatment throughput since 2010 from 40 to 32 patients per 8 h work shift (WS8). Thanks to hypo-fractionation, such an efficiency drop did not affect NPY, estimating 693 ± 28 NPY/WS8, regardless of the evaluation time. Each newly installed machine was shown to add 540 NPY, while absorbing 0.78 ± 0.04 WS8. The COVID-19 pandemic brought an overall reduction of 3.7% of patients and a reduction of 0.8 fractions/patient, to mitigate patient crowding in the department.
Conclusions:
The evolution of therapy protocols towards hypo-fractionation was supported by the use of proper technology. The characteristics of this process were quantified considering time progression and organizational aspects. This strategy optimized resources while enabling broader access to advanced radiation therapy. To truly value the benefit of hypo-fractionation, a reimbursement policy should focus on the patient rather than individual treatment fractionation.
... Another modality to reduce treatment time besides HFRT is hypofractionated accelerated radiation therapy. The use of hypofractionated protocols has been established in several randomized controlled trials [55][56][57][58]. This method is however primarily recommended for elderly patients and its role in the treatment of GB in younger individuals and those with good prognosis requires further research [59]. ...
Background and purpose
The standard treatment of glioblastoma patients consists of surgery followed by normofractionated radiotherapy (NFRT) with concomitant and adjuvant temozolomide chemotherapy. Whether accelerated hyperfractionated radiotherapy (HFRT) yields comparable results to NFRT in combination with temozolomide has only sparsely been investigated. The objective of this study was to compare NFRT with HFRT in a multicenter analysis.
Materials and methods
A total of 484 glioblastoma patients from four centers were retrospectively pooled and analyzed. Three-hundred-ten and 174 patients had been treated with NFRT (30 × 1.8 Gy or 30 × 2 Gy) and HFRT (37 × 1.6 Gy or 30 × 1.8 Gy twice/day), respectively. The primary outcome of interest was overall survival (OS) which was correlated with patient-, tumor- and treatment-related variables via univariable and multivariable Cox frailty models. For multivariable modeling, missing covariates were imputed using multiple imputation by chained equations, and a sensitivity analysis was performed on the complete-cases-only dataset.
Results
After a median follow-up of 15.7 months (range 0.8–88.6 months), median OS was 16.9 months (15.0–18.7 months) in the NFRT group and 14.9 months (13.2–17.3 months) in the HFRT group (p = 0.26). In multivariable frailty regression, better performance status, gross-total versus not gross-total resection, MGMT hypermethylation, IDH mutation, smaller planning target volume and salvage therapy were significantly associated with longer OS (all p < 0.01). Treatment differences (HFRT versus NFRT) had no significant effect on OS in either univariable or multivariable analysis.
Conclusions
Since HFRT with temozolomide was not associated with worse OS, we assume HFRT to be a potential option for patients wishing to shorten their treatment time.
... Another modality to reduce treatment time besides HFRT is hypofractionated accelerated radiation therapy. The use of hypofractionated protocols has been established in several randomized controlled trials [54][55][56][57]. This method is however primarily recommended for elderly patients and its role in the treatment of GB in younger individuals and those with good prognosis requires further research [58]. ...
Background and purpose
The standard treatment of glioblastoma (GB) patients consists of surgery followed by normofractionated radiotherapy (NFRT) with concomitant and adjuvant temozolomide chemotherapy. Whether accelerated hyperfractionated radiotherapy (HFRT) yields comparable results to NFRT in combination with temozolomide has only sparsely been investigated. The objective of this study was to compare NFRT with HFRT in a multicenter analysis.
Materials and methods
A total of 484 GB patients from four centers were retrospectively pooled and analyzed. 310 and 174 patients had been treated with NFRT (30×1.8Gy or 30×2Gy) and HFRT (37×1.6Gy or 30×1.8Gy twice/day), respectively. The primary outcome of interest was overall survival (OS) which was correlated with patient-, tumor- and treatment-related variables via univariable and multivariable Cox frailty models. For multivariable modeling, missing covariates were imputed using multiple imputation by chained equations, and a sensitivity analysis was performed on the complete-cases-only dataset.
Results
After a median follow-up of 15.7 months (range 0.8-88.6 months), median OS was 16.9 months (15.0-18.7 months) in the NFRT group and 14.9 months (13.2-17.3 months) in the HFRT group (p=0.26). In multivariable frailty regression, better performance status, complete versus not complete resection, MGMT hypermethylation, IDH mutation, smaller planning target volume, no steroid administration, and salvage therapy were significantly associated with longer OS (all p<0.01). Treatment differences (HFRT versus NFRT) had no significant effect on OS in either univariable or multivariable analysis.
Conclusions
This analysis suggests that HFRT and temozolomide is a safe option for patients wishing to shorten their treatment time and does not affect OS.
... To date, high-dose RT at a total dose of 90 Gy (90 Gy in 45 Fr) has led to a remarkable improvement in outcomes [22,23]. Hypofractionated RT (40 Gy in 15 Fr or 60 Gy in 15 Fr) has led to a reduction in the burden of RT on the elderly [24,25]. In most cases, local recurrence originated from the excision cavity in the high-dose irradiation region [1,22,23]. ...
To treat malignant glioma, standard fractionated radiotherapy (RT; 60 Gy/30 fractions over 6 weeks) was performed post-surgery in combination with temozolomide to improve overall survival. Malignant glioblastoma recurrence rate is extremely high, and most recurrent tumors originate from the excision cavity in the high-dose irradiation region. In our previous study, protoporphyrin IX physicochemically enhanced reactive oxygen species generation by ionizing radiation and combined treatment with 5-aminolevulinic acid (5-ALA) and ionizing radiation, while radiodynamic therapy (RDT) improved tumor growth suppression in vivo in a melanoma mouse model. We examined the effect of 5-ALA RDT on the standard fractionated RT protocol using U251MG- or U87MG-bearing mice. 5-ALA was orally administered at 60 or 120 mg/kg, 4 h prior to irradiation. In both models, combined treatment with 5-ALA slowed tumor progression and promoted regression compared to treatment with ionizing radiation alone. The standard fractionated RT protocol of 60 Gy in 30 fractions with oral administration of 120 and 240 mg/kg 5-ALA, the human equivalent dose of photodynamic diagnosis, revealed no significant increase in toxicity to normal skin or brain tissue compared to ionizing radiation alone. Thus, RDT is expected to enhance RT treatment of glioblastoma without severe toxicity under clinically feasible conditions.
... Evidence regarding the predictive and prognostic value is still lacking, and its use in planning local treatments, such as surgery and radiation therapy, is debated. In 2013, we designed a Phase II trial to evaluate the role of a short RT course in newly diagnosed GBM patients, and results are already published [17]. All patients underwent a hypofractionated RT (HFRT) scheme following different entities of surgical resection. ...
... The original study design was previously published [17]. In the present analysis, we evaluated MET PET's role in eventually integrating the EOR definition by MRI, the correlation between CERTV and BTV, and the variation of RT target volume delineation concerning the BTV. ...
... Newly diagnosed GBMs patients enrolled in the phase II clinical study received a different amount of surgical resection followed by HFRT with concomitant and adjuvant temozolomide chemotherapy. Considering that the primary aim was to evaluate the benefit of a short course of RT, the results obtained were highly satisfactory with a low rate of side effects [17]. Indeed, although an extensive surgical resection was performed in the largest number of patients treated, no major perioperative morbidity occurred, and adjuvant treatments were started without delays. ...
(1) Background: We investigated the role of [11C]-methionine PET in a cohort of newly diagnosed glioblastoma multiforme (GBM) patients to evaluate whether it could modify the extent of surgical resection and improve radiation therapy volume delineation. (2) Methods: Newly diagnosed GBM patients, ages 18–70, with a Karnofsky performance scale (KPS) ≥ 70 with available MRI and [11C]-methionine PET were included. Patients were treated with different amounts of surgical resection followed by radio-chemotherapy. The role of [11C]-methionine PET in surgical and RT planning was analyzed. A threshold of SUVmax was searched. (3) Results: From August 2013 to April 2016, 93 patients were treated and included in this analysis. Residual tumor volume was detected in 63 cases on MRI and in 78 on [11C]-methionine PET, including 15 receiving gross total resection. The location of uptake was mainly observed in FLAIR abnormalities. [11C]-methionine uptake changed RT volume in 11% of patients. The presence of [11C]-methionine uptake in patients receiving GTR proved to influence survival (p = 0.029). The threshold of the SUVmax conditioning outcome was five. (4) Conclusions: [11C]-methionine PET allowed to detect areas at higher risk of recurrence located in FLAIR abnormalities in patients affected by GBM. A challenging issue is represented by integrating morphological and functional imaging to better define the extent of surgical resection to perform.
... [13] The factors influencing treatment outcomes of glioblastoma are Karnofsky Performance Status, MGMT methylation status and aggressive surgical resection. [14] Concomitant hypofractionated RT and TMZ with simultaneous integrated boost therapy was analyzed in 24 glioblastoma patients by Scoccianti et al. This novel approach may be suitable and logical treatment approach for patients with good prognosis. ...
Background:
The main goal of our study is to comparatively evaluate outcomes of hypofractionation and long-term fractionation with temozolomide (TMZ) in glioblastoma patients older than 65 years.
Methods:
Eighty patients with glioblastoma meeting the eligibility criteria of >65 years of age, the Karnofsky performance score (KPS) >60, no previous radiotherapy (RT) to the brain referred to our department between October 2009 and October 2016 for adjuvant chemoradiotherapy after surgery were studied. The first group of patients received a dose of 6000 cGy in 30 fractions and the second group was delivered 4000 cGy in 15 fractions All patients used TMZ concomitantly with RT. We used the paired t-test and the Wilcoxon signed-rank test with Statistical Package for the Social Sciences, version 15.0 (SPSS, Inc., Chicago, IL, USA) software for statistical analysis.
Results:
Forty-six patients were men (57.5%), and 34 patients (42.5%) were woman. Median age was 68 years (range 66-87). Median KPS was 75 (range 60-100). Median follow-up time was 12 months (range 6-30). Median overall survival was 15.2 months and 14.3 months for patients with hypofractionation and conventional fractionation, respectively, with no statistical significance (P = 0.13).
Conclusion:
Hypofractionation should be recommended to the elderly glioblastoma patients older than 65 years because of the short treatment time, reduced acute adverse effects of both TMZ and RT compared to long-term fractionation.
... This allowed us to care for a similar number of cancer patients with fewer visits to the cancer center, smaller staff compliment and reduced potential exposure to COVID-19 throughout the study period. These changes affected several tumor sites including: single fractions for most palliation (Chow et al., 2019), 5-day adjuvant breast cancer treatments (Brunt et al., 2020), 5-day neoadjuvant rectal cancer treatments (Cisel et al., 2019), and 3-week radical brain tumor treatments (Navarria et al., 2017). ...
Purpose
Our institution operates a remote radiation oncology service in Northern Ontario, Canada. Since the start of the COVID-19 pandemic, this center has operated without radiation oncologists on site due to safety precautions and this study seeks to understand the impact of this shift.
Methods
Departmental level data reports, were used to investigate differences in metrics between April-May of 2019 and April-May 2020. These metrics include the total number of referrals received, average wait time from referral to consult, the number of cases that underwent peer review prior to beginning treatment, the total number of fractions given over each time period, patient reported outcomes, and patient satisfaction. We also examined the importance of physical examinations and the use of stereotactic ablative radiotherapy treatment.
Results
There was an observed decrease in the number of referrals received, total number of fractions administered, and number of patients providing patient reported outcomes. We observed no change in patient wait times, cases undergoing peer review prior to commencing treatment, and overall patient satisfaction. Challenges were identified in the collection of patient reported outcomes and the conduction of physical examinations.
Conclusion
This paper provides proof of concept that a radiation clinic can function entirely virtually in the short term without sacrificing patient satisfaction, efficiency or safety.
... It suffers hidden agenda bias, and variability due to random error related to problems with unintentional data entry oversight and neglect. Sixteen studies evaluated altered fractionation or dose of radiation for GBM [127,131-133, 135, 136,1 38-148]. of which only one was a phase III trial [142], five were phase I trials [127,132,135,136,139] one was phase I/II trial [131], five were phase II [133,[143][144][145][146] and the other four were retrospective studies [138,141,147,148]. All of these were subject to bias related patient selection, loss or lack of information collection, data interpretation, and choice to publish. ...
... Due to the phase I nature of the study design, it yielded class III data. There are several phase II trial evaluated hypofractionated radiation treatment [143][144][145][146]. However, all these were single arm trials, as a result, only provides class II evidence, and warrant further evaluation. ...
... Wang et al. focused on elderly population, and showed there is no significant difference with hypofractionated radiation and conventional radiation treatment [149]. And Navarria performed a propensity score matched analysis, showed there is no significant difference between these two radiation regimens [144,147]. However, these are retrospective studies, only provide class III evidence. ...
Target population
These recommendations apply to adult patients with newly diagnosed or suspected glioblastoma.
Imaging
Question What imaging modalities are in development that may be able to provide improvements in diagnosis, and therapeutic guidance for individuals with newly diagnosed glioblastoma?
Recommendation
Level III: It is suggested that techniques utilizing magnetic resonance imaging for diffusion weighted imaging, and to measure cerebral blood and magnetic spectroscopic resonance imaging of N-acetyl aspartate, choline and the choline to N-acetyl aspartate index to assist in diagnosis and treatment planning in patients with newly diagnosed or suspected glioblastoma.
Surgery
Question What new surgical techniques can be used to provide improved tumor definition and resectability to yield better tumor control and prognosis for individuals with newly diagnosed glioblastoma?
Recommendations
Level II: The use of 5-aminolevulinic acid is recommended to improve extent of tumor resection in patients with newly diagnosed glioblastoma.
Level II: The use of 5-aminolevulinic acid is recommended to improve median survival and 2 year survival in newly diagnosed glioblastoma patients with clinical characteristics suggesting poor prognosis.
Level III: It is suggested that, when available, patients be enrolled in properly designed clinical trials assessing the value of diffusion tensor imaging in improving the safety of patients with newly diagnosed glioblastoma undergoing surgery.
Neuropathology
Question What new pathology techniques and measurement of biomarkers in tumor tissue can be used to provide improved diagnostic ability, and determination of therapeutic responsiveness and prognosis for patients with newly diagnosed glioblastomas?
Recommendations
Level II: Assessment of tumor MGMT promoter methylation status is recommended as a significant predictor of a longer progression free survival and overall survival in patients with newly diagnosed with glioblastoma.
Level II: Measurement of tumor expression of neuron-glia-2, neurofilament protein, glutamine synthetase and phosphorylated STAT3 is recommended as a predictor of overall survival in patients with newly diagnosed with glioblastoma.
Level III: Assessment of tumor IDH1 mutation status is suggested as a predictor of longer progression free survival and overall survival in patients with newly diagnosed with glioblastoma.
Level III: Evaluation of tumor expression of Phosphorylated Mitogen-Activated Protein Kinase protein, EGFR protein, and Insulin-like Growth Factor-Binding Protein-3 is suggested as a predictor of overall survival in patients with newly diagnosed with glioblastoma.
Radiation
Question What radiation therapy techniques are in development that may be used to provide improved tumor control and prognosis for individuals with newly diagnosed glioblastomas?
Recommendations
Level III: It is suggested that patients with newly diagnosed glioblastoma undergo pretreatment radio-labeled amino acid tracer positron emission tomography to assess areas at risk for tumor recurrence to assist in radiation treatment planning.
Level III: It is suggested that, when available, patients be with newly diagnosed glioblastomas be enrolled in properly designed clinical trials of radiation dose escalation, altered fractionation, or new radiation delivery techniques.
Chemotherapy
Question What emerging chemotherapeutic agents or techniques are available to provide better tumor control and prognosis for patients with newly diagnosed glioblastomas?
Recommendation
Level III: As no emerging chemotherapeutic agents or techniques were identified in this review that improved tumor control and prognosis it is suggested that, when available, patients with newly diagnosed glioblastomas be enrolled in properly designed clinical trials of chemotherapy.
Molecular and targeted therapy
Question What new targeted therapy agents are available to provide better tumor control and prognosis for individuals with newly diagnosed glioblastomas?
Recommendation
Level III: As no new molecular and targeted therapies have clearly provided better tumor control and prognosis it is suggested that, when available, patients with newly diagnosed glioblastomas be enrolled in properly designed clinical trials of molecular and targeted therapies
Immunotherapy
Question What emerging immunotherapeutic agents or techniques are available to provide better tumor control and prognosis for patients with newly diagnosed glioblastomas?
Recommendation
Level III: As no immunotherapeutic agents have clearly provided better tumor control and prognosis it is suggested that, when available, patients with newly diagnosed glioblastomas be enrolled in properly designed clinical trials of immunologically-based therapies.
Novel therapies
Question What novel therapies or techniques are in development to provide better tumor control and prognosis for individuals with newly diagnosed glioblastomas?
Recommendations
Level II: The use of tumor-treating fields is recommended for patients with newly diagnosed glioblastoma who have undergone surgical debulking and completed concurrent chemoradiation without progression of disease at the time of tumor-treating field therapy initiation.
Level II: It is suggested that, when available, enrollment in properly designed studies of vector containing herpes simplex thymidine kinase gene and prodrug therapies be considered in patients with newly diagnosed glioblastoma.
... Twenty one non-comparative studies assessed the impact of hypofractionation in newly diagnosed glioblastoma patients in 22 treatment arms [4,6,8,11,12,20,[26][27][28][29][30][31][32][33][34][35][36][37][38][39][40] (Additional file 3). Outcomes were compared with the ones of the Stupp trial, which is currently considered as the reference in the management of first-line glioblastoma [2]. ...
... Among the 22 treatment arms, 11 tested a concurrent chemoradiation (temozolomide or temozolomide-bevacizumab) [11,[26][27][28][29][30][31][32][33][34]40]. Radiotherapy was hSRT in 2 arms whereas 9 arms used conventional techniques. ...
Background:
Glioblastoma multiforme (GBM) has a poor prognosis despite a multi modal treatment that includes normofractionated radiotherapy. So, various hypofractionated alternatives to normofractionated RT have been tested to improve such prognosis. There is need of systematic review and meta-analysis to analyse the literature properly and maybe generalised the use of hypofractionation. The aim of this study was first, to perform a meta-analysis of all controlled trials testing the impact of hypofractionation on survival without age restriction and secondly, to analyse data from all non-comparative trials testing the impact of hypofractionation, radiosurgery and hypofractionated stereotactic RT in first line.
Materials/methods:
We searched Medline, Embase and Cochrane databases to identify all publications testing the impact of hypofractionation in glioblastoma between 1985 and March 2020. Combined hazard ratio from comparative studies was calculated for overall survival. The impact of study design, age and use of adjuvant temozolomide was explored by stratification. Meta-regressions were performed to determine the impact of prognostic factors.
Results:
2283 publications were identified. Eleven comparative trials were included. No impact on overall survival was evidenced (HR: 1.07, 95%CI: 0.89-1.28) without age restriction. The analysis of non-comparative literature revealed heterogeneous outcomes with limited quality of reporting. Concurrent chemotherapy, completion of surgery, immobilization device, isodose of prescription, and prescribed dose (depending on tumour volume) were poorly described. However, results on survival are encouraging and were correlated with the percentage of resected patients and with patients age but not with median dose.
Conclusions:
Because few trials were randomized and because the limited quality of reporting, it is difficult to define the place of hypofactionation in glioblastoma. In first line, hypofractionation resulted in comparable survival outcome with the benefit of a shortened duration. The method used to assess hypofractionation needs to be improved.
... Given the significant OS advantage of a combined modality regimen, short-course regimens of RT alone (40 Gy in 15 fractions, 34 Gy in 10 or 25 Gy in 5 fractions) should be reserved for elderly and frail poor performance status patients, and the addition of TMZ to 40 Gy in 15 fractions considered on a case-by-case basis. Unfortunately, there are limited data available supporting hypofractionation in HGG patients <60 years old with a good performance status, 17,18 and as such, we make expert-based consensus statements in this cohort with respect to considering hypofractionated RT (± TMZ) (see Table 1). It is our opinion that these recommendations balance the benefits of completing a course of Downloaded from https://academic.oup.com/neuro-oncology/advance-article-abstract/doi/10.1093/neuonc/noaa113/5829911 by Technische Universitaet Muenchen user on 08 June 2020 ...
Background:
Because of the increased risk in cancer patients of developing complications caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), physicians have to balance the competing risks of the negative impact of the pandemic and the primary tumor. In this consensus statement, an international group of experts present mitigation strategies and treatment guidance for patients suffering from high grade gliomas (HGG) during the coronavirus disease 2019 (COVID-19) pandemic.
Method / results:
16 international experts in the treatment of HGG contributed to this consensus-based practice recommendation including neuro-oncologists, neurosurgeons, radiation -oncologists and a medical physicist. Generally, treatment of neuro-oncological patients cannot be significantly delayed and initiating therapy should not be outweighed by COVID-19. We present detailed interdisciplinary treatment strategies for molecular subgroups in two pandemic scenarios, a scale-up phase and a crisis phase.
Conclusion:
This practice recommendation presents a pragmatic framework and consensus-based mitigation strategies for the treatment of HGG patients during the SARS-CoV-2 pandemic.
