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      The Impact of Timing of Concurrent Chemoradiation in Patients With High-Grade Glioma in the Era of the Stupp Protocol

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          Abstract

          Background: The purpose of this study is to provide a critical review of current evidence for the impact of time to initiation of chemoradiation on overall survival in patients with newly diagnosed high-grade gliomas treated with radiation and concurrent temozolomide chemotherapy.

          Methods: A literature search was conducted using PubMed/MEDLINE and EMBASE databases. Studies were included if they provided separate analysis for patients treated with current standard of care: radiation and concurrent temozolomide. Bias assessment was performed for each included study using the Newcastle-Ottawa Assessment Scale, with Karnofsky Performance Status (KPS) and extent of resection used for comparability.

          Results: The initial search yielded 575 citations. Based on the inclusion/exclusion criteria, a total of 10 retrospective cohort studies were included in this review for a total of 30,298 patients. Of these, one study described an indirect relationship between time to initiation of treatment and overall survival. One study found decreased survival only with patients with significantly longer time to treatment. Four studies found no significant effect of time to treatment on overall survival. The four remaining studies found that patients with moderate time to initiation had the best overall survival.

          Conclusion: This review provides evidence that moderate time to initiation of chemoradiotherapy in patients with high-grade gliomas does not lead to a significant decrease in overall survival, though the effect of significant delays in treatment initiation remains unclear.

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          Tumor regrowth between surgery and initiation of adjuvant therapy in patients with newly diagnosed glioblastoma.

          K Lamborn, Stefan Berger, Scott Vandenberg … (2009)
          To assess incidence and degree of regrowth in glioblastoma between surgery and radiation therapy (RT) and to correlate regrowth with presurgical imaging and survival, we examined images of 32 patients with newly diagnosed glioblastoma who underwent MR spectroscopic imaging (MRSI), perfusion-weighted imaging (PWI), and diffusion-weighted imaging (DWI) prior to surgery, after surgery, and prior to RT/temozolomide. Contrast enhancement (CE) in the pre-RT MR image was compared with postsurgical DWI to differentiate tumor growth from postsurgical infarct. MRSI and PWI parameters were analyzed prior to surgery and pre-RT. Postsurgical MRI indicated that 18 patients had gross total and 14 subtotal resections. Twenty-one patients showed reduced diffusion, and 25 patients showed new or increased CE. In eight patients (25%), the new CE was confined to areas of postsurgical reduced diffusion. In the other 17 patients (53%), new CE was found to be indicative of tumor growth or a combination of tumor growth and surgical injury. Higher perfusion and creatine within nonenhancing tumor in the presurgery MR were associated with subsequent tumor growth. High levels of choline and reduced diffusion in pre-RT CE suggested active metabolism and tumor cell proliferation. Median survival was 14.6 months in patients with interim tumor growth and 24 months in patients with no growth. Increased volume or new onset of CE between surgery and RT was attributed to tumor growth in 53% of patients and was associated with shorter survival. This suggests that reducing the time between surgery and adjuvant therapy may be important. The acquisition of metabolic and physiologic imaging data prior to adjuvant therapy may also be valuable in assessing regions of new CE and nonenhancing tumor.
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            Delay in radiotherapy shortens survival in patients with high grade glioma.

            Chris Irwin, Martin K. Hunn, Gordon Purdie … (2007)
            Fractionated external beam radiotherapy is an important component of standard treatment for high grade glioma. Due to resource constraints, patients may experience delays in receiving treatment. The purpose of this study was to evaluate the effect of radiotherapy waiting time on survival in patients with high grade glioma. A retrospective analysis was performed of 172 patients with a histological diagnosis of WHO Grade 3 or 4 Astrocytoma who had undergone surgery at Wellington Hospital between 1993 and 2003, and who subsequently underwent radiotherapy. Time to radiotherapy after surgery varied from 7 days to over 16 weeks. Multiple Cox regression analysis showed that age, performance status, tumour grade, extent of surgical resection, radiotherapy dose, and time to radiotherapy from day of surgery were all independently related to survival. Every additional week of delay until the start of radiotherapy increases the risk of death (hazard ratio) by 8.9% (95%CI 2.0%-16.1%). A 6 week delay in starting radiotherapy (from 2 weeks post-op to 8 weeks) reduces median survival by 11 weeks for a typical patient. Delay in radiotherapy results in a clinically significant reduction in survival. These findings have implications for resource allocation and for the design of clinical trials.
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              The effect of waiting for radiotherapy for grade III/IV gliomas.

              Viet Do, Val Gebski, Michael Barton (2000)
              To determine the effect of waiting time for radiotherapy on the overall survival of patients with high-grade gliomas. We examined records of patients with grade III/IV gliomas who were referred to radiotherapy after surgery or biopsy - ECOG 50 Gy, no interstitial or radiosurgery boost. Waiting time was defined in two ways, time from biopsy to radiotherapy and time from presentation to radiotherapy department to start of radiotherapy. There were 182 patients in the study having a median survival of 8.5 months, with a median follow up of 10.5 months. The group comprised of 63 (35%) grade III and 119 (65%) grade IV gliomas. Median times and ranges from biopsy and presentation to treatment were 26 days (4-78 days) and 15 days (1-62 days), respectively. The median dose was 60 Gy in a median of 30 fractions over a median of 46 days. Tumour progression before and during radiotherapy occurred in seven patients (4%) and 19 patients (11%), respectively. One hundred and seventy-nine patients died of disease. The seven patients whose tumour progressed before radiotherapy were excluded from the analysis of prognostic variables. In a multivariate analysis the variables that were significantly associated with worse survival were older age, reduced dose and prolonged waiting time from presentation. The risk of death increased by 2% for each day of waiting for radiotherapy. The study showed longer waiting time from presentation at radiotherapy department to treatment to be a significant predictor of overall survival for patients with high-grade glioma.
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                Author and article information

                Contributors
                Journal
                Journal ID (nlm-ta): Front Oncol
                Journal ID (iso-abbrev): Front Oncol
                Journal ID (publisher-id): Front. Oncol.
                Title: Frontiers in Oncology
                Publisher: Frontiers Media S.A.
                ISSN (Electronic): 2234-943X
                Publication date (Electronic): 27 March 2019
                Publication date Collection: 2019
                Volume: 9
                Electronic Location Identifier: 186
                Affiliations
                [1] 1School of Medicine and Dentistry, University of Rochester Medical Center , Rochester, NY, United States
                [2] 2Department of Public Health Sciences, University of Rochester Medical Center , Rochester, NY, United States
                [3] 3Department of Neurosurgery, University of Rochester Medical Center , Rochester, NY, United States
                [4] 4Department of Radiation Oncology, University of Rochester Medical Center , Rochester, NY, United States
                Author notes

                Edited by: Erik P. Sulman, New York University, United States

                Reviewed by: Glenn J. Lesser, Wake Forest Baptist Medical Center, United States; Yoshua Esquenazi, University of Texas Health Science Center at Houston, United States

                *Correspondence: Kwanza T. Warren kwanza_warren@ 123456urmc.rochester.edu

                This article was submitted to Neuro-Oncology and Neurosurgical Oncology, a section of the journal Frontiers in Oncology

                Article
                DOI: 10.3389/fonc.2019.00186
                PMC ID: 6445963
                PubMed ID: 30972296
                SO-VID: c95d3f47-3030-4a8f-bf73-810e9e38d0af
                Copyright © Copyright © 2019 Warren, Liu, Liu, Milano and Walter.
                License:

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                History
                Date received : 26 November 2018
                Date accepted : 04 March 2019
                Page count
                Figures: 2, Tables: 4, Equations: 0, References: 41, Pages: 9, Words: 6060
                Categories
                Subject: Oncology
                Subject: Systematic Review

                ScienceOpen disciplines: Oncology & Radiotherapy
                Keywords: gliobastoma,high-grade glioma,chemoradiation,timing,wait time
                Data availability:
                ScienceOpen disciplines: Oncology & Radiotherapy
                Keywords: gliobastoma, high-grade glioma, chemoradiation, timing, wait time

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