Skip to main content

Locally dose-escalated radiotherapy may improve intracranial local control and overall survival among patients with glioblastoma

Abstract

Background

The dismal overall survival (OS) prognosis of glioblastoma, even after trimodal therapy, can be attributed mainly to the frequent incidence of intracranial relapse (ICR), which tends to present as an in-field recurrence after a radiation dose of 60 Gray (Gy). In this study, molecular marker-based prognostic indices were used to compare the outcomes of radiation with a standard dose versus a moderate dose escalation.

Methods

This retrospective analysis included 156 patients treated between 2009 and 2016. All patients were medically fit for postoperative chemoradiotherapy. In the dose-escalation cohort a simultaneous integrated boost of up to 66 Gy (66 Gy RT) within small high-risk volumes was applied. All other patients received daily radiation to a total dose of 60 Gy or twice daily to a total dose of 59.2 Gy (60 Gy RT).

Results

A total of 133 patients received standard 60 Gy RT, while 23 received 66 Gy RT. Patients in the 66 Gy RT group were younger (p <  0.001), whereas concomitant temozolomide use was more frequent in the 60 Gy RT group (p <  0.001). Other intergroup differences in known prognostic factors were not observed. Notably, the median time to ICR was significantly prolonged in the 66 Gy RT arm versus the 60 Gy RT arm (12.2 versus 7.6 months, p = 0.011), and this translated to an improved OS (18.8 versus 15.3 months, p = 0.012). A multivariate analysis revealed a strong association of 66 Gy RT with a prolonged time to ICR (hazard ratio = 0.498, p = 0.01) and OS (hazard ratio = 0.451, p = 0.01). These differences remained significant after implementing molecular marker-based prognostic scores (ICR p = 0.008, OS p = 0.007) and propensity-scored matched pairing (ICR p = 0.099, OS p = 0.023).

Conclusion

Radiation dose escalation was found to correlate with an improved time to ICR and OS in this cohort of glioblastoma patients. However, further prospective validation of these results is warranted.

Background

The field of glioblastoma (GBM) treatment has seen little progress since the implementation of temozolomide (TMZ) and the establishment of trimodal therapy, which comprises surgery, adjuvant radiation with concurrent TMZ and TMZ maintenance, as standard therapy for medically fit patients by Stupp and colleagues in 2005 [1]. Tumor treating fields (TTF) during maintenance TMZ therapy have been shown to further improve patient outcome in a phase III trial compared to standard trimodal therapy [2]. However due to reimbursement issues and a potential negative impact on quality of life the addition of TTF is not yet nationwide standard of care. Currently, a standard total radiation dose of 60 Gy is administered via single-dose fractionated radiotherapy in 2-Gy fractions concomitantly with TMZ. However, this standard is based on older studies of adjuvant radiotherapy alone in which a dose-response relationship was identified for doses up to 60 Gy [3, 4].

GBM is considered a radioresistant malignancy, and most patients die from local, intracranial relapse. Therefore, radiotherapeutic dose escalation strategies have long been a topic of interest. Studies of patients treated with 2-dimensional (2D) or 3D planed radiotherapy during the pre-TMZ era reported that doses exceeding 60 Gy did not yield survival benefits; rather, patients faced an increased risk of radiation-induced brain necrosis [4, 5]. However, modern radiation techniques could potentially allow dose escalation within smaller high-risk regions with lower dose accumulations in surrounding normal brain tissues, thus decreasing the risk of symptomatic brain necrosis [6]. Several more recent studies on state-of the art dose-escalation have reported inconclusive results. One phase I study demonstrated the feasibility of dose escalation via intensity modulated radiotherapy (IMRT) without concurrent TMZ [7], while another reported promising results with a radiation dose escalation up to 81 Gy via IMRT with concomitant TMZ [8]. A phase-I/II study with a carbon ion boost suggested an association of improved progression-free survival and OS with higher carbon boost doses [9]. However, a prospective phase II study and several retrospective analyses of radiation dose escalations > 60 Gy with concomitant TMZ did not find substantial improvements in overall survival (OS) [10,11,12]. Accordingly, 60 Gy remains the standard radiation dose.

The conflicting findings of prior studies might be attributable to the wide variety in clinical outcome and treatment response of histologically confirmed GBM after radiotherapy and TMZ. These differences can only be partially explained by established baseline characteristics of patient, tumor and surgical resection status [13]. Accordingly, genetic alterations and molecular markers are considered important, with a high prognostic impact. Of these, O(6)-methylguanine DNA methyltransferase (MGMT) promoter methylation is likely the best known molecular marker [14]. Several other molecular parameters, such as isocitrate-dehydrogenase (IDH), have been identified. Accordingly, GBM is among the first cancers with a molecular rather than classical histological classification [15,16,17].

Recently, MGMT and IDH were used together with other known prognostic factors to identify subgroups of GBM patients with significantly different treatment outcomes after standard trimodal treatment [18]. The current study aimed to investigate whether a moderate state-of-the-art radiation dose escalation would correlate with an improved survival outcome in patients stratified according to these novel molecular markers.

Methods

Surgical treatment and radiation dose prescription

This retrospective analysis included patients treated between January 2009 and October 2016. All treatment decisions were made by an interdisciplinary tumor board.

In the standard group radiotherapy was administered in 2-Gy fractions to a total dose of 60 Gy or twice-per-day (BID) in 1.6 Gy fractions to a total dose of 59.2 Gy. These two regimens have been described in detail elsewhere and were proven to be equally efficacious in terms of OS and intracerebral failure. Patients treated with either regimen were combined in a single group for analysis (abbreviated as 60 Gy RT for ease of reading) [19].

Patients were offered an experimental regimen in which moderate dose escalation was achieved via a simultaneous integrated boost (SIB) to the macroscopic tumor region/resection cavity. This option was based on earlier in-house experiences with moderate dose escalation for GBM [5]. These patients received a 66-Gy SIB to the pre-surgical gross tumor volume (GTV) or residual disease/suspected residual tumor and 60 Gy to the surrounding planning target volume (66 Gy RT).

Treatment planning

Computed tomography (CT) with a thermoplastic mask was performed for RT planning. Additionally, gadolinium-enhanced magnetic resonance imaging (MRI) was performed before and after surgical resection and registered rigidly to the planning CT. These MRI scans were used to delineate the target volumes and organs at risk (OAR). The GTV was defined as the combined volume of the postoperative surgical cavity, with or without residual tumor lesions, and the tumor extension on preoperative T1-weighted gadolinium-enhanced MRI. Diffusion-weighted imaging (DWI) findings were also used to estimate the GTV. The SIB volume comprised the part of the GTV identified as either residual disease or potential residual disease (e.g. eloquent areas or other critical structures that usually impede radical surgery) and was defined in collaboration with the respective neurosurgeon. Regarding the clinical target volume (CTV), a 2-cm symmetrical margin around the GTV was added with reduced margins to anatomical boundaries such as bone, tentorium or falx. For the planning target volume (PTV), an additional 0.2–0.5 cm margin was added (depending on the treatment and modality used for position verification).

IMRT was applied using a 6-MV linear accelerator with multileaf collimators or the Novalis™ therapy system (Varian, USA; Brainlab, Heimstetten, Germany). Some patients were treated using helical tomotherapy. For all patients except those undergoing tomotherapy, treatment comprised either step-and-shoot IMRT or volumetric arc therapy.

Assessment of prognostic factors, toxicities and follow-up

According to a previous publication, patients were classified into prognostic groups (RPA [recursive partitioning analysis] class 1, 2 or 3), which were determined based on KPS, completeness of resection, IDH and MGMT status and age, as described elsewhere in detail [18]. Patient files were screened retrospectively for the analysis of toxicities, which were usually scored weekly during treatment according to the common toxicity criteria for adverse events (CTCAE) 4.0. Follow-up consisted of clinical and MRI examinations every 2–3 months. Additional amino acid positron emission tomography (PET) scans were performed if the MRI investigations were inconclusive.

Statistical analyses and software

The patient and tumor characteristics were compared between the two treatment groups using the chi-squared test (categorical variables) or Mann–Whitney U test (continuous variables). The Kaplan–Meier method was used to calculate the OS and intracranial control (ICC) probabilities from the day of surgery, and the log-rank test was used for intergroup comparisons of these probabilities. Univariate and multivariate analyses were performed using Cox regression analyses; here, parameters with significance according to the univariate analysis (p <  0.05) were included in the multivariate analysis. Propensity-scored matching (PSM) was performed using the nearest-neighbor matching method with a caliper of 0.4 and matching ratio of 1:2 (dose escalation versus no dose escalation). All statistical analyses were performed using SPSS version 24.0 (IBM Inc., Armonk, NY, USA) and R version 3.2.5 (R Foundation for Statistical Computing, Vienna, Austria) [20].

Results

Table 1 presents the baseline characteristics for both treatment groups. The patients receiving standard doses and dose escalation differed significantly in terms of age, with a median age of 51 years in the 66 Gy RT versus 62 years in the 60 Gy RT group (p <  0.001). In contrast, the RPA class and resection completeness did not differ between the groups. Patients in the 60 Gy RT group more frequently received concomitant TMZ (p <  0.001) and had a slightly larger PTV volumes.

Table 1 Patient and tumor characteristics

In the experimental patient cohort, the median SIB volume was 19.2 cm3 (ccm, range: 2.6–83.6 cm3). Dose escalation within a small volume was generally well tolerated, as indicated by a lack of differences in acute toxicity between the 60 Gy RT and 66 Gy RT groups. Additional file 1: Table S1 summarizes the observed acute toxicities within the 66 Gy RT group. Although none of these patients developed symptomatic radiation-induced brain necrosis, follow-up MRI revealed asymptomatic brain necrosis in one patient, who was referred for a histological exclusion of relapse. The biopsy confirmed radionecrosis with no signs of tumor recurrence.

Regarding survival, the median OS durations were 15.3 months (range 2 to 48.1 months) in the 60 Gy RT group and 18.8 months (range: 5 to 37.8 months) in the 66 Gy RT group, and the median intervals to intracranial relapse were 7.6 (range: 0.3 to 30.8 months) and 12.2 (range: 3.5 to 37.4) months, respectively. Both differences were significant, as shown in Fig. 1. To rule out confounding errors an additional comparison of the experimental cohort with the normofractionated cohort was performed. This analysis also confirmed the significant benefit regarding OS (p = 0.009) and intracranial relapse (p = 0.015) for patients treated with 66 Gy RT (Additional file 2: Figure S1). The RPA classification revealed a non-significant difference according to RPA. Additional file 3: Figure S2 depicts the corresponding Kaplan–Meier survival curves for the whole cohort. An additional analysis stratified by RPA group revealed increases in the durations of OS and ICC in the 66 Gy RT group relative to other groups (p = 0.007 for OS and p = 0.008 for ICC). Figure 2 and Additional file 4: Figure S3 present the Kaplan–Meier curves for OS and ICC by RPA class.

Fig. 1
figure 1

Probabilities of intracranial control (left) and overall survival among patients receiving a standard radiation dose (60 Gy radiotherapy [RT]) and those receiving dose-escalated radiotherapy (66 Gy RT). Median time to intracranial relapse: 225 days (60 Gy) versus 289 days (66 Gy), p = 0.011. Median OS: 397 days (60 Gy) versus 533 days (66 Gy), p = 0.012

Fig. 2
figure 2

Overall survival probabilities of patients receiving a standard radiation dose (60 Gy radiotherapy [RT]) and those receiving dose-escalated radiotherapy (66 Gy RT) after stratification by recursive partitioning analysis (RPA) prognostic groups 1–3, n.a. = insufficient data for allocation. p = 0.007 for OS and p = 0.008 for ICC pooled according to RPA classification

In the univariate analysis of factors related to OS, dose escalation correlated with an increase in OS [hazard ratio (HR) = 0.47, range: 0.26–0.86, p = 0.007], whereas a higher age (HR = 1.02, range: 1.001–1.04, p = 0.03) and worse resection status (HR = 1.36, range: 1.02–1.80, p = 0.04) were associated with a decreased OS. Furthermore, an inverse trend was observed between the RPA class and OS (HR = 1.18, range: 0.98–1.42, p = 0.07). Dose escalation (p = 0.023) and resection status (p = 0.028) remained significantly associated with OS in the multivariate analysis. A further univariate analysis of factors affecting ICC revealed strong associations with an escalated radiation dose (HR = 0.51, range: 0.30–0.87, p = 0.007) and resection status (HR = 1.35, range: 1.03–1.77, p = 0.031). Both factors remained significantly associated with ICC in the multivariate analysis (p = 0.010 and 0.021, respectively). Table 2 summarizes the results of the univariate and multivariate analyses.

Table 2 Univariate and multivariate Cox regression analyses of OS and ICC

To exclude bias associated with the retrospective study design, 142 patients with fully available data were subjected to an additional PSM analysis of the following matching parameters: age, tumor location, resection type, TMZ use and RPA class (which additionally implemented information about the KPS and IDH and MGMT statuses). Here, the PSM revealed a significant difference in OS between the 66 Gy RT and 60 Gy RT groups (p = 0.023), while the 66 Gy RT group exhibited a trend towards better ICC (p = 0.099). Figure 3 presents the Kaplan-Meier plots for the propensity-matched patients. Additional file 5: Table S2 presents patient and tumor characteristics after propensity scored matching.

Fig. 3
figure 3

Probabilities of intracranial control (left) and overall survival patients receiving a standard radiation dose (60 Gy radiotherapy [RT]) and those receiving dose-escalated radiotherapy (66 Gy RT) after propensity-scored matching. Median OS: 457 days (60 Gy) versus 535 days (66 Gy), p = 0.023. Median time to intracranial relapse: 225 days (60 Gy) versus 301 days (66 Gy), p = 0.09

Discussion

This report describes the initial experiences with state-of-the-art radiation dose escalation via a SIB approach in GBM patients stratified by molecular prognostic markers. Although the study was limited by its retrospective design, we attempted to reduce the associated bias through stratification according to molecularly defined prognostic groups and a PSM analysis, which both confirmed the initial finding that moderate dose escalation within small high-risk volumes yielded significant improvements in OS and ICC. Furthermore, this survival benefit was maintained when patients were grouped according to established prognostic groups based mainly upon the MGMT and IDH status. Nonetheless even RPA classification might not be able to completely rule out misbalances between the two treatment groups, especially as patients in the 66 Gy RT group showed a tendency towards a higher rate of MGMT promoter methylation. Additionally other potentially prognostic factors such as the exact anatomical tumor location [21,22,23] microRNA profile [24, 25], neutrophil to lymphocyte ratio [26] and functional imaging parameters [27] were not considered for risk stratification. We additionally did not assess other potential confounders such as the postoperative waiting period, although a large retrospective analysis of GBM patients revealed that this factor had no impact on patient survival [28]. Furthermore, we did not analyze the concomitant use of corticosteroid therapy, which may have a detrimental effect on OS [29]. Still, we note that this potential association remains controversial and is not proven by prospective data.

Although the groups in our study differed slightly with respect to age, the observed improvements in ICC and OS were not likely attributable to this difference.

Patients receiving standard-dose radiation had a median OS of 15.3 months, which was consistent with the OS reported by Stupp for the chemoradiotherapy arm (14.6 months) [1]. Furthermore, although patients in the 66 Gy RT arm were younger, concomitant TMZ use was less frequent in this group, mainly because of comorbidities or a poorer KPS. We further note that the radiation techniques did not differ between the groups: all patients received IMRT, which is potentially superior to 3D conformal radiotherapy [30]. Another difference is the PTV which was slightly larger in the 60 Gy RT group. This could mean that patients within the 66 Gy RT group presented smaller tumors, which is a potential confounder. However all but two patients in the 66 Gy RT were treated with high precision radiation therapy (Novalis) with reduced CTV-PTV margins (2 mm instead of 5 mm). Therefore the small (absolute) difference of PTVs might most likely be due to these circumstances and was therefore not confounding the results. This is supported by univariate analyses on OS and ICC that did not show an association with PTV volume.

Although GBM cells, and particularly GBM stem cells, are generally considered radioresistant [31], a dose-response relationship has been identified for these tumors [32, 33]. Therefore, efforts to improve therapeutic outcomes should include radiation dose escalation, among other strategies. The Radiation Therapy Oncology Group (RTOG) study 83–02, which was conducted during the pre-TMZ era, identified a dose-dependency among GBM patients receiving a hyperfractionated accelerated dose-escalated radiation schedule [34]. In contrast, the randomized RTOG 93–05 trial did not observe an improved outcome after dose escalation by a stereotactic boost [35].

In the TMZ era, several studies on the effect of radiation dose escalation have yielded conflicting results. One single-arm study reported a median OS of 14.8 months after a dose escalation to 72 Gy with an amino acid PET-based integrated boost. However, that study included only 22 patients, and therefore the results should be interpreted cautiously [10]. In a retrospective analysis, no significant survival benefit was observed among 128 patients receiving dose-escalated radiotherapy when compared to 81 patients receiving a standard radiation dose. In that analysis, however, the prescribed doses within the escalated arm differed widely (61–76 Gy), and the median 2-Gy equivalent dose of 64 Gy was relatively low [12]. Another retrospective analysis of 49 patients receiving dose escalations of up to 70 Gy also failed to report a significant survival benefit relative to a 60-Gy radiation dose [11]. In that analysis, however, the 60-Gy cohort had a relatively long OS of 18.4 months. Additionally, a statistical trend toward improved survival was observed for patients receiving an escalated dose to the subventricular zones was found, suggesting that the area of dose escalation is a critical factor in terms of efficacy. Several other publications highlighted that the dose to the subventricular zones may be an important factor in terms of outcome [36, 37]. This was not assessed in our study and is a potential confounder.

A study on upfront dose escalation by 6 to 14 Gy Gamma Knife radiotherapy reported very promising OS results with a median OS time of 23 months in a relatively large cohort of 174 patients [38].

The use of amino acid PET to determine target volumes for dose escalation appears to be promising. A recent study of a relatively high PET-based dose escalation reported a median OS of 20.0 months [39], and Tsien and colleagues reported a similarly promising survival outcome after dose escalation (20.1 months) [8]. The neurooncologic community eagerly awaits the results of larger ongoing studies investigating the association of amino acid PET tracer uptake with recurrence patterns (https://clinicaltrials.gov/ct2/show/NCT01873469?term=NCT01873469&rank=1), as these are expected to direct future studies of image-guided dose escalation. According to several studies, amino-acid PET-based treatment planning yields larger high-risk volumes [40] that correlate more strongly with recurrent disease than MRI-based delineation [8, 41,42,43]. Given the prognostic relevance of the metabolic active tumor volume [27, 44], the selective dose escalation of PET-defined volumes appears promising.

Conclusion

In conclusion, our data suggest an association of modern approaches to radiation dose escalation within small high-risk regions with improved survival in GBM patients. However, these findings should be interpreted cautiously, given the retrospective nature of the data. Further validation through prospective trials, ideally combined with functional imaging, is warranted.

Abbreviations

2D:

2-dimensional

BID:

Twice-per-day

ccm:

Cubic centimeters

CT:

Computed tomography

CTV:

Clinical target volume

DWI:

Diffusion-weighted imaging

GBM:

Glioblastoma

GTV:

Gross tumor volume

Gy:

Gray

HR:

Hazard ratio

ICC:

Intracranial control

ICR:

Intracranial relapse

IDH:

Isocitrate-dehydrogenase

IMRT:

Intensity modulated radiotherapy

MGMT:

O(6)-methylguanine DNA methyltransferase

MRI:

Magnetic resonance imaging

OAR:

Organs at risk

OS:

Overall survival

PET:

Positron emission tomography

PSM:

Propensity-scored matching

PTV:

Planning target volume

RPA:

Recursive partitioning analysis

SIB:

Simultaneous integrated boost

TMZ:

Temozolomide

References

  1. Stupp R, Mason WP, van den Bent MJ, Weller M, Fisher B, Taphoorn MJB, et al. Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med. 2005;352:987–96.

    Article  CAS  Google Scholar 

  2. Stupp R, Taillibert S, Kanner AA, Kesari S, Steinberg DM, Toms SA, et al. Maintenance therapy with tumor-treating fields plus Temozolomide vs Temozolomide alone for glioblastoma: a randomized clinical trial. JAMA. 2015;314:2535–43.

    Article  CAS  Google Scholar 

  3. Walker AM, Suit HD. Assessment of local tumor control using censored tumor response data. Int J Radiat Oncol Biol Phys. 1983;9:383–6.

    Article  CAS  Google Scholar 

  4. Miller PJ, Hassanein RS, Giri PG, Kimler BF, O’Boynick P, Evans RG. Univariate and multivariate statistical analysis of high-grade gliomas: the relationship of radiation dose and other prognostic factors. Int J Radiat Oncol Biol Phys. 1990;19:275–80.

    Article  CAS  Google Scholar 

  5. Graf R, Hildebrandt B, Tilly W, Sreenivasa G, Ullrich R, Felix R, et al. Dose-escalated conformal radiotherapy of glioblastomas -- results of a retrospective comparison applying radiation doses of 60 and 70 Gy. Onkologie. 2005;28:325–30.

    PubMed  Google Scholar 

  6. Tsien C, Moughan J, Michalski JM, Gilbert MR, Purdy J, Simpson J, et al. Phase I three-dimensional conformal radiation dose escalation study in newly diagnosed glioblastoma: radiation therapy oncology group trial 98-03. Int J Radiat Oncol Biol Phys. 2009;73:699–708.

    Article  Google Scholar 

  7. Monjazeb AM, Ayala D, Jensen C, Case LD, Bourland JD, Ellis TL, et al. A phase I dose escalation study of hypofractionated IMRT field-in-field boost for newly diagnosed glioblastoma multiforme. Int J Radiat Oncol Biol Phys. 2012;82:743–8.

    Article  Google Scholar 

  8. Tsien CI, Brown D, Normolle D, Schipper M, Piert M, Junck L, et al. Concurrent temozolomide and dose-escalated intensity-modulated radiation therapy in newly diagnosed glioblastoma. Clin Cancer Res. 2012;18:273–9.

    Article  CAS  Google Scholar 

  9. Mizoe J-E, Tsujii H, Hasegawa A, Yanagi T, Takagi R, Kamada T, et al. Phase I/II clinical trial of carbon ion radiotherapy for malignant gliomas: combined X-ray radiotherapy, chemotherapy, and carbon ion radiotherapy. Int J Radiat Oncol Biol Phys. 2007;69:390–6.

    Article  CAS  Google Scholar 

  10. Piroth MD, Pinkawa M, Holy R, Klotz J, Schaar S, Stoffels G, et al. Integrated boost IMRT with FET-PET-adapted local dose escalation in glioblastomas. Results of a prospective phase II study. Strahlenther Onkol. 2012;188:334–9.

    Article  CAS  Google Scholar 

  11. Kusumawidjaja G, Gan PZH, Ong WS, Teyateeti A, Dankulchai P, Tan DYH, et al. Dose-escalated intensity-modulated radiotherapy and irradiation of subventricular zones in relation to tumor control outcomes of patients with glioblastoma multiforme. Onco Targets Ther. 2016;9:1115–22.

    CAS  PubMed  PubMed Central  Google Scholar 

  12. Badiyan SN, Markovina S, Simpson JR, Robinson CG, DeWees T, Tran DD, et al. Radiation therapy dose escalation for glioblastoma multiforme in the era of temozolomide. Int J Radiat Oncol Biol Phys. 2014;90:877–85.

    Article  Google Scholar 

  13. Thumma SR, Fairbanks RK, Lamoreaux WT, Mackay AR, Demakas JJ, Cooke BS, et al. Effect of pretreatment clinical factors on overall survival in glioblastoma multiforme: a surveillance epidemiology and end results (SEER) population analysis. World J Surg Oncol. 2012;10:75.

    Article  Google Scholar 

  14. Hegi ME, Diserens A-C, Gorlia T, Hamou M-F, de Tribolet N, Weller M, et al. MGMT gene silencing and benefit from temozolomide in glioblastoma. N Engl J Med. 2005;352:997–1003.

    Article  CAS  Google Scholar 

  15. Crespo I, Vital AL, Gonzalez-Tablas M, Patino Mdel C, Otero A, Lopes MC, et al. Molecular and genomic alterations in glioblastoma Multiforme. Am J Pathol. 2015;185:1820–33.

    Article  CAS  Google Scholar 

  16. Olar A, Aldape KD. Using the molecular classification of glioblastoma to inform personalized treatment. J Pathol. 2014;232:165–77.

    Article  Google Scholar 

  17. Hartmann C, Hentschel B, Wick W, Capper D, Felsberg J, Simon M, et al. Patients with IDH1 wild type anaplastic astrocytomas exhibit worse prognosis than IDH1-mutated glioblastomas, and IDH1 mutation status accounts for the unfavorable prognostic effect of higher age: implications for classification of gliomas. Acta Neuropathol. 2010;120:707–18.

    Article  Google Scholar 

  18. Wee CW, Kim E, Kim N, Kim IA, Kim TM, Kim YJ, et al. Novel recursive partitioning analysis classification for newly diagnosed glioblastoma: A multi-institutional study highlighting the MGMT promoter methylation and IDH1 gene mutation status. Radiother Oncol. 2017; Available from: http://linkinghub.elsevier.com/retrieve/pii/S0167814017300919. [cited 27 Mar 2017].

  19. Kaul D, Florange J, Badakhshi H, Grün A, Ghadjar P, Exner S, et al. Accelerated hyperfractionation plus temozolomide in glioblastoma. Radiat Oncol. 2016;11:70.

    Article  Google Scholar 

  20. Thoemmes F., Liao W. Propensity Score Matching (with multilevel data) Using SPSS and R. 2013.

  21. Liang TH-K, Kuo S-H, Wang C-W, Chen W-Y, Hsu C-Y, Lai S-F, et al. Adverse prognosis and distinct progression patterns after concurrent chemoradiotherapy for glioblastoma with synchronous subventricular zone and corpus callosum invasion. Radiother Oncol. 2016;118:16–23.

    Article  Google Scholar 

  22. Adeberg S, König L, Bostel T, Harrabi S, Welzel T, Debus J, et al. Glioblastoma recurrence patterns after radiation therapy with regard to the subventricular zone. Int J Radiat Oncol Biol Phys. 2014;90:886–93.

    Article  Google Scholar 

  23. Weinberg BD, Boreta L, Braunstein S, Cha S. Location of subventricular zone recurrence and its radiation dose predicts survival in patients with glioblastoma. J Neuro-Oncol. 2018; Available from: http://link.springer.com/10.1007/s11060-018-2822-8. [cited 16 Mar 2018].

  24. Niyazi M, Zehentmayr F, Niemöller OM, Eigenbrod S, Kretzschmar H, Schulze-Osthoff K, et al. MiRNA expression patterns predict survival in glioblastoma. Radiat Oncol. 2011;6:153.

    Article  CAS  Google Scholar 

  25. Chang JH, Hwang YH, Lee DJ, Kim DH, Park JM, Wu H-G, et al. MicroRNA-203 modulates the radiation sensitivity of human malignant glioma cells. Int J Radiat Oncol Biol Phys. 2016;94:412–20.

    Article  CAS  Google Scholar 

  26. Mason M, Maurice C, McNamara MG, Tieu MT, Lwin Z, Millar B-A, et al. Neutrophil-lymphocyte ratio dynamics during concurrent chemo-radiotherapy for glioblastoma is an independent predictor for overall survival. J Neuro-Oncol. 2017;132:463–71.

    Article  Google Scholar 

  27. Poulsen SH, Urup T, Grunnet K, Christensen IJ, Larsen VA, Jensen ML, et al. The prognostic value of FET PET at radiotherapy planning in newly diagnosed glioblastoma. Eur J Nucl Med Mol Imaging. 2017;44:373–81.

    Article  CAS  Google Scholar 

  28. Seidlitz A, Siepmann T, Löck S, Juratli T, Baumann M, Krause M. Impact of waiting time after surgery and overall time of postoperative radiochemotherapy on treatment outcome in glioblastoma multiforme. Radiat Oncol. 2015;10:172.

    Article  Google Scholar 

  29. Pitter KL, Tamagno I, Alikhanyan K, Hosni-Ahmed A, Pattwell SS, Donnola S, et al. Corticosteroids compromise survival in glioblastoma. Brain. 2016;139:1458–71.

    Article  Google Scholar 

  30. Thibouw D, Truc G, Bertaut A, Chevalier C, Aubignac L, Mirjolet C. Clinical and dosimetric study of radiotherapy for glioblastoma: three-dimensional conformal radiotherapy versus intensity-modulated radiotherapy. J Neuro-Oncol. 2018;137:429–38.

    Article  Google Scholar 

  31. Bao S, Wu Q, McLendon RE, Hao Y, Shi Q, Hjelmeland AB, et al. Glioma stem cells promote radioresistance by preferential activation of the DNA damage response. Nature. 2006;444:756–60.

    Article  CAS  Google Scholar 

  32. Pedicini P, Fiorentino A, Simeon V, Tini P, Chiumento C, Pirtoli L, et al. Clinical radiobiology of glioblastoma multiforme: estimation of tumor control probability from various radiotherapy fractionation schemes. Strahlenther Onkol. 2014;190:925–32.

    Article  Google Scholar 

  33. Jones B, Sanghera P. Estimation of radiobiologic parameters and equivalent radiation dose of cytotoxic chemotherapy in malignant glioma. Int J Radiat Oncol Biol Phys. 2007;68:441–8.

    Article  Google Scholar 

  34. Werner-Wasik M, Scott CB, Nelson DF, Gaspar LE, Murray KJ, Fischbach JA, et al. Final report of a phase I/II trial of hyperfractionated and accelerated hyperfractionated radiation therapy with carmustine for adults with supratentorial malignant gliomas. Radiation therapy oncology group study 83-02. Cancer. 1996;77:1535–43.

    Article  CAS  Google Scholar 

  35. Souhami L, Seiferheld W, Brachman D, Podgorsak EB, Werner-Wasik M, Lustig R, et al. Randomized comparison of stereotactic radiosurgery followed by conventional radiotherapy with carmustine to conventional radiotherapy with carmustine for patients with glioblastoma multiforme: report of radiation therapy oncology group 93-05 protocol. Int J Radiat Oncol Biol Phys. 2004;60:853–60.

    Article  Google Scholar 

  36. Adeberg S, Harrabi SB, Bougatf N, Bernhardt D, Mohr A, Rieber J, et al. Do increased doses to stem-cell niches during radiation therapy improve glioblastoma survival? Stem Cells Int. 2016;2016:8793462.

    Article  Google Scholar 

  37. Chen L, Guerrero-Cazares H, Ye X, Ford E, McNutt T, Kleinberg L, et al. Increased subventricular zone radiation dose correlates with survival in glioblastoma patients after gross total resection. Int J Radiat Oncol Biol Phys. 2013;86:616–22.

    Article  Google Scholar 

  38. Duma CM, Kim BS, Chen PV, Plunkett ME, Mackintosh R, Mathews MS, et al. Upfront boost gamma knife “leading-edge” radiosurgery to FLAIR MRI-defined tumor migration pathways in 174 patients with glioblastoma multiforme: a 15-year assessment of a novel therapy. J Neurosurg. 2016;125:40–9.

    PubMed  Google Scholar 

  39. Miwa K, Matsuo M, Ogawa S, Shinoda J, Asano Y, Ito T, et al. Hypofractionated high-dose irradiation with positron emission tomography data for the treatment of glioblastoma multiforme. Biomed Res Int. 2014;2014:407026.

    Article  Google Scholar 

  40. Munck Af Rosenschold P, Costa J, Engelholm SA, Lundemann MJ, Law I, Ohlhues L, et al. Impact of [18F]-fluoro-ethyl-tyrosine PET imaging on target definition for radiation therapy of high-grade glioma. Neuro-oncology. 2015;17:757–63.

    Article  Google Scholar 

  41. Piroth MD, Galldiks N, Pinkawa M, Holy R, Stoffels G, Ermert J, et al. Relapse patterns after radiochemotherapy of glioblastoma with FET PET-guided boost irradiation and simulation to optimize radiation target volume. Radiat Oncol. 2016;11:87.

    Article  Google Scholar 

  42. Harat M, Małkowski B, Makarewicz R. Pre-irradiation tumour volumes defined by MRI and dual time-point FET-PET for the prediction of glioblastoma multiforme recurrence: a prospective study. Radiother Oncol. 2016;120:241–7.

    Article  Google Scholar 

  43. Weber DC, Casanova N, Zilli T, Buchegger F, Rouzaud M, Nouet P, et al. Recurrence pattern after [(18)F]fluoroethyltyrosine-positron emission tomography-guided radiotherapy for high-grade glioma: a prospective study. Radiother Oncol. 2009;93:586–92.

    Article  Google Scholar 

  44. Piroth MD, Holy R, Pinkawa M, Stoffels G, Kaiser HJ, Galldiks N, et al. Prognostic impact of postoperative, pre-irradiation (18)F-fluoroethyl-l-tyrosine uptake in glioblastoma patients treated with radiochemotherapy. Radiother Oncol. 2011;99:218–24.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We are grateful to Cornelia Cordes for collecting patient files.

Funding

Not applicable.

Availability of data and materials

Data in the manuscript are available by contacting the corresponding author.

Author information

Authors and Affiliations

Authors

Contributions

SZ provided ideas, performed the analysis and drafted the manuscript. JF collected patient data. PW, RG, MM, JO, HB and VB were responsible for patient treatment and planning. PW, PG and DK provided ideas, supervised the analysis and interpretation of the data and reviewed the manuscript. All authors read and approved the final manuscript.

Corresponding author

Correspondence to David Kaul.

Ethics declarations

Ethics approval and consent to participate

Written informed consent was acquired from all patients with respect to RT treatment and clinical data management for research purposes. The local ethics board approved the study.

Consent for publication

All authors approved the final version of the manuscript.

Competing interests

The authors declare that they have no competing interests.

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Additional files

Additional file 1:

Table S1. Radiation induced side effects 66 Gy RT. (DOCX 15 kb)

Additional file 2:

Figure S1. Intracranial control probability and overall survival probability according to the three different radiation schedules: 2 Gy daily up to 60 Gy (60 Gy), 60 Gy with 66 Gy simultaneous integrated bosst (66 Gy) and bi-daily 1.6 Gy to 59.2 Gy (59.2 Gy BID). P-values are given for comparison between 60 Gy and 66 Gy. (PDF 36 kb)

Additional file 3:

Figure S2. Intracranial control probability and overall survival probability according to RPA classification for all patients. (PDF 32 kb)

Additional file 4:

Figure S3. Intracranial control probability according to RPA classification separated for patients treated with standard dose (60Gy) or with dose escalation by simultaneous integrated boost (66 Gy). (PDF 37 kb)

Additional file 5:

Table S2. Patient and tumor characteristics after propensity scored matching. (DOCX 22 kb)

Rights and permissions

Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Zschaeck, S., Wust, P., Graf, R. et al. Locally dose-escalated radiotherapy may improve intracranial local control and overall survival among patients with glioblastoma. Radiat Oncol 13, 251 (2018). https://doi.org/10.1186/s13014-018-1194-8

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1186/s13014-018-1194-8

Keywords