Radiotherapy and Oncology 142 (2020) 162–167

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Radiotherapy and Oncology

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Original Article

Intraoperative radiotherapy for glioblastoma: an international pooled

analysis
Gustavo R. Sarria a, Elena Sperk a,1, Xiaodi Han b,c,d, Gustavo J. Sarria e,f, Frederik Wenz a,g,
Stefanie Brehmer h, Bing Fu c, Siming Min c, Hongjun Zhang c, Shusen Qin c, Xiaoguang Qiu i,
Daniel Hänggi h, Yasser Abo-Madyan a, David Martinez e, Carla Cabrera f, Frank A. Giordano a,⇑
a
Department of Radiation Oncology, University Medical Center Mannheim, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany; b Department of Neurosurgery
Beijing Tiantan Hospital, Capital Medical University, Beijing; c Department of Neurosurgery, Beijing Tiantan Puhua Hospital; d China National Clinical Research Center for Neurological
Diseases, Beijing, China; e Department of Radiotherapy, Oncosalud – AUNA; f Department of Radiotherapy, Instituto Nacional de Enfermedades Neoplasicas, Lima, Peru; g University
Medical Center Freiburg, Freiburg, Germany; h Department of Neurosurgery, University Medical Center Mannheim, Medical Faculty Mannheim, Heidelberg University, Mannheim,
Germany; and i Department of Radiotherapy, Beijing Tiantan Puhua Hospital, Capital Medical University, Beijing, China

a r t i c l e i n f o a b s t r a c t

Article history: Purpose: To report the results of the first international pooled analysis of patients with glioblastoma trea-
Received 15 July 2019 ted with intraoperative radiotherapy (IORT) in addition to standard of care therapy.
Received in revised form 27 August 2019 Methods: Data from 51 patients treated at five centers in Germany, China and Peru were analyzed. All
Accepted 24 September 2019
patients underwent tumor resection followed by a single application of IORT (10–40 Gy, prescribed to
Available online 16 October 2019
the applicator surface) with low-energy X-rays. Thereafter, standard adjuvant radiochemotherapy and
maintenance chemotherapy were applied. Factors of interest were overall survival (OS), progression-
Keywords:
free survival (PFS), local PFS (L-PFS; defined as appearance of new lesions
1 cm to the cavity border)
Intraoperative radiotherapy
Dose-escalated boost
and distant PFS (D-PFS; lesions >1 cm). The same endpoints were estimated at 1-, 2- and 3-years using
Glioblastoma the Kaplan-Meier method. Additionally, rates and severity (as per Common Terminology Criteria for
Adverse Events Version 5.0) of radionecrosis (RN) were analyzed.
Results: The median age was 55 years (range: 16–75) and the median Karnofsky Performance Status was
80 (20–100). At a median follow-up of 18.0 months (2–42.4), the median OS, PFS, L-PFS and D-PFS were
18.0 months (95% CI: 14.7–21.3), 11.4 months (95%CI: 7.58–15.22), 16 months (95%CI: 10.21–21.8) and
30.0 months (95%CI: 18.59 – 41.41), respectively. The estimated 1-, 2- and 3-year OS, PFS, L-PFS and D-
PFS were 79.5%, 38.7% and 25.6%; 46.2%, 29.4%, and 5.9%; 60.9, 37.9%, and 12.6%; and 76.7%, 65.0%, and
39.0% respectively. First progression occurred locally in only 35.3% of cases. Grade 1 RN was detected
in 7.8% and grade 3 in 17.6% of the patients. No grade 4 toxicity was reported and no treatment-
related deaths occurred.
Conclusion: Compared to historical data, this pooled analysis suggests improved efficacy and safety of
IORT with low-energy X-rays for newly diagnosed glioblastoma. Prospective data is warranted to confirm
these findings.
Ó 2019 The Author(s). Published by Elsevier B.V. Radiotherapy and Oncology 142 (2020) 162–167 This is
an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

Glioblastoma (GB) represents the most frequent primary malig- as young age, high Karnofsky performance status (KPS) and hyper-
nancy of the brain in adults, accounting for more than half of all methylation of the O6-methylguanine-DNA-methyltransferase
gliomas [1]. Survival times are still narrow and range between 1 (MGMT) promoter suffer from tumor recurrence, usually occurring
and 3 years [2–6]. Even patients with favorable risk factors, such 14–17 months after therapy [2,6].
Despite technical advances, including neurophysiology-,
neuronavigation- and fluorescence-guided gross total resection
⇑ Corresponding author at: Department of Radiation Oncology, University (GTR); local tumor re-growth remains the most frequent pattern
Medical Center Mannheim, Medical Faculty Mannheim, University of Heidelberg, of failure [7–10]. As tumors start repopulating the cavity immedi-
Germany Theodor-Kutzer-Ufer 1-3, 68167 Mannheim, Germany.
ately after surgery and even during radiotherapy [11,12], we pro-
E-mail addresses: [email protected] (E. Sperk), [email protected] (F.
A. Giordano).
posed to overcome this spatial and temporal miss using
1
Statistical analysis author: Department of Radiation Oncology, University Medical additional low-energy intraoperative radiotherapy (IORT) [13],
Center Mannheim, Medical Faculty Mannheim, University of Heidelberg, Theodor- which is applied immediately after surgery and, due to the unique
Kutzer-Ufer 1-3; 68167 Mannheim, Germany.

https://doi.org/10.1016/j.radonc.2019.09.023
0167-8140/Ó 2019 The Author(s). Published by Elsevier B.V.
This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
 G.R. Sarria et al. / Radiotherapy and Oncology 142 (2020) 162–167 163

physical characteristics of low-energy photons, restricted to the ged from 10 to 40 Gy, with most of the patients receiving 10 Gy.
surgical margin. Dose distribution curves are shown in Figs. 1 and 2 for a 3 cm
Recently a prospective, single-arm phase I/II study was con- diameter Spherical applicator. Adjuvant EBRT was applied in all
ducted to determine the safety and efficacy of IORT with low- but one patient and 44 of 51 patients received temozolomide-
energy X-rays added to standard of care adjuvant therapy based chemotherapy (Table 1).
(radiochemotherapy and maintenance chemotherapy) [14]. It
was shown that the addition of IORT was not only tolerable, but
also yielded a median local progression-free survival of roughly Treatment outcomes
18 months despite a high portion of patients with post-operative
residual disease (13 of 15) and unmethylated MGMT promoters At a median follow-up of 18 months (range: 2–42.4 months),
(10 of 15) in the trial [15]. the median OS was 18.0 months (95% confidence interval [CI]:
The encouraging data from this trial has not only prompted the 14.7–21.3 months; Fig. 3a). The OS rates estimated at 12, 24, and
initiation of a randomized phase III trial (NCT02685605), but also a 36 months were 79.5%, 38.7% and 25.6% respectively. The median
variety of single-arm mono-institutional studies. We here present (overall) PFS was 11.4 months (95%CI: 7.6–15.2; Fig. 3b) and the
an international pooled analysis of patients treated with low- PFS rates at 12, 24, and 36 months were 46.2%, 29.4%, and 5.9%.
energy IORT at five institutions from three different countries, in The median L-PFS was 16 months (95%CI: 10.2–21.8; Fig. 3c), with
addition to standard of care therapy. It resembles the largest cohort annual estimated L-PFS rates of 60.9, 37.9%, and 12.6%. The median
of patients that have received this therapy so far. D-PFS was 30 months (95%CI: 18.6–41.4, Fig. 3d), with estimated

Methods

Patients from five centers (located in Germany, Peru and China)

were retrospectively included in this analysis. All patients were
diagnosed with suspected GB/high-grade glioma in pre-treatment
magnetic resonance imaging (MRI) and subsequently underwent
surgery. Only patients with confirmed pathology diagnosis of GB
were included in the analysis. IORT was delivered as described pre-
viously after frozen sections supported the preliminary diagnosis
of glioblastoma [14,15]. In brief, 50-kV X-rays (INTRABEAM, Carl
Zeiss Meditec AG, Oberkochen, Germany) were applied using
spherical applicators (size range 1.5–5 cm) at dose levels ranging
from 10 to 40 Gy prescribed to the surgical margin (0 cm depth,
i.e. the applicator surface). Following surgery, all patients received
standard-of-care adjuvant therapy, consisting of 60 Gy intensity-
modulated or volumetric-modulated arc (IMRT-VMAT) external-
beam radiotherapy (EBRT) and concomitant temozolomide
chemotherapy followed by maintenance temozolomide
chemotherapy (2). Thereafter, response was assessed at 8–12 week
intervals using multiparametric MRI, and updated RANO criteria
[16].
Factors of interest were median overall survival (OS), median
progression-free survival (PFS), median local PFS (L-PFS, with local
recurrence being defined as tumor recurrence within 1 cm to the
cavity margin), median distant PFS (D-PFS, with a distant recur-
rence being defined as any new lesion occurring >1 cm from the
cavity margin), and radionecrosis rates (RNR). Multiparametric
MRI included Perfusion sequences to account for pseudoprogres-
sion, according to clinical criteria and local follow-up protocol. In
addition, estimated cumulative rates for these endpoints were cal-
culated for 12, 24 and 36 months using the Kaplan–Meier method.
Severity was assessed based on Common Terminology Criteria for
Adverse Events (CTCAE) version 5.0. All statistical analyses were
performed using SPSS (V. 24.0; IBM, Armonk, NY).

Results

Patients characteristics
A total of 51 patients were treated with IORT in addition to
standard-of-care. The median age was 55 years (range: 16–
75 years) and the median KPS was 80 (20–100). MGMT promoter
hypermethylation was absent in 39.2% of patients. IDH1 was found
to be wild type in 76.5% and mutated in 9.8% of patients. Satellite
lesions were present in 15.7% of the patients. Depending on local Fig. 1. Isodose distribution in parenchyma for 30 Gy prescribed at applicatoŕs
practices, site-specific protocols and/or constraints of organs-at- surface. Delivery of ~20% of total prescribed dose after 1 cm, might vary with
risk (mainly chiasm, optical nerves, brain stem) applied doses ran- applicator size.
164 Intraoperative radiotherapy for glioblastoma

Fig. 2. DVH graphic with organs-at-risk dose.

Table 1
Baseline patient characteristics and treatments. Data are either N or median unless
rates of 76.7%, 65.0%, and 39.0% per year. First progression occurred
stated otherwise. Legend: MGMT, O6-methylguanine-DNA-methyltransferase; IDH1, locally in only 35.3% of cases (Table 2).
Isocitrate dehydrogenase 1; IORT, intraoperative radiotherapy; EBRT, external-beam
radiotherapy.
Toxicity profile
Characteristics N/Median (Range) %
Median Age (years) 55 (16–75) Radionecrosis was judged to be present in 13 patients (25.5%),
Median KPS 80 (20–100) which is in line with previous findings in a phase I/II trial (15).
Gender RN was scored to be of grade 1 RN in 4 patients (7.8%) and of grade
Male 28 54.9
3 in 9 patients (17.6%). There was no significant relation between
Female 23 45.1
Satellite Lesionsy RN and OS, PFS and L-PFS; however, a difference in D-PFS was
Present 8 15.7 found, favoring patients that developed RN against those who did
Absent 42 82.3 not, as no patient from this group (n = 9) developed distant pro-
Unknown 1 2
gression and 15 from the non-radionecrosis (n = 42) group pre-
MGMT
Methylated 17 33.3 sented this toxicity (p = 0.047). No grade 4 or 5 toxicity related to
Unmethylated 20 39.2 IORT was found in this cohort and no treatment-related deaths
Unknown 14 27.5 occurred (Table 3).
IDH1 Status
IDH1 wild type 39 76.5
IDH1 R132H mutation 5 9.8 Discussion
Unknown 7 13.7
IORT Doseà
10 Gy 23 45.1 Surgery resembles one of the most important components of
20 Gy 9 17.6 glioblastoma therapy and novel technology may allow to identify
30 Gy 15 29.4 and resect almost all macroscopically visible tumor [17]. Although
40 Gy 4 7.8 it appears sound that there is a direct correlation between the
IORT delivery time (min) 17 (5–58)
amount of tumor removed and outcome [18], surgery-related neu-
Adjuvant EBRT*
Yes 50 98 rological deficits may ultimately counteract all benefits [19], which
No 1 2 often results in ‘‘maximum safe” than ‘‘gross total” resections.
Chemotherapy# However, even after (macroscopic) complete resection of glioblas-
Yes 44 86.3
toma, a considerable number of tumor cells will remain in the cav-
No 3 5.9
Unknown 4 7.8
ity [20]. These cells are capable to rapidly re-populate the margin
as demonstrated in comparative analyses of early post-operative
y
Defined as separate T1-contrast-enhancing lesion within the edema visible in T2. and pre-radiotherapy scans [11,12].
à
Prescribed to the applicator surface.
*
Total dose 60 Gy, given in 20 fractions.
Few improvements of glioblastoma therapy were achieved over
#
Includes concomitant (75 mg/kg/d) and maintenance (150–200 mg/m2, 5/28 the past decades: Patients with favorable (epi)genomic profile
scheme) temozolomide chemotherapy. [21,22] benefit from the addition of temozolomide (2) and lomus-
 G.R. Sarria et al. / Radiotherapy and Oncology 142 (2020) 162–167 165

Fig. 3. Kaplan–Meier curves for Overall Survival (a), Progression-free survival (b), Local recurrence-free survival (c), and Distant recurrence-free survival (d).

tine (6) to radiotherapy. Alternating electric fields may delay torical data as the median PFS in the benchmarking EORTC trial
tumor growth by inhibiting cell division independent of the molec- was 6.9 months (2) with no notable improvements in standard-
ular subtype [23]. The general approach of external-beam radio- of-care arms in contemporary studies [4,5]. Despite the limitations
therapy (EBRT), however, has not significantly changed since the of our study, the reported OS rate at 3 years (25.6%) reinforces the
1980s, where a regimen of 60 Gy given in 30 fractions of 2 Gy improved outcomes hypothesis, as the aforementioned seminal
was established [24,25]. Although some technological advances trial reported similar outcomes after 2 years follow-up (26.5%).
(such as intensity-modulated radiotherapy) increased the confor- One of the main concerns about achieving a radical dose at
mity of EBRT, dose escalation studies yielded conflicting results brain tissue is the development of radionecrosis. This side effect
in terms of overall survival benefit [26–30]. has been the limiting burden for dose escalation, although
Intraoperative radiotherapy does not require extra radiation to brachytherapy dose-escalation reports suggested less severe com-
travel through healthy tissue as compared to EBRT, thus allowing plications rates than only EBRT-based approaches, with incidences
for local dose escalation at the site of most likely recurrence [34– ranging from 4 to 27%, [26,37]. The rate of radionecrosis in this
36]. In contrast to intraoperative electron radiotherapy (IOeRT), analysis (25.1%) was seen to be higher than after standard of care
that may leave several aspects of the cavity uncovered [31,32], a (5–10%) [38] but lower than in the INTRAGO trial (33%) or after
more intuitive approach is to modify the dose distribution and to interstitial brachytherapy (~50%) [39]. However, in the light of a
spherically cover the cavity with low-energy X-rays [33]. In a potential correlation between radionecrosis and improved out-
recent phase I/II trial, this novel approach of local dose escalation come [40] and the availability of a drug (bevacizumab) that highly
yielded a median progression free survival of 11.2 months and a effective terminates symptomatic radionecrosis [41], we consider
median local progression-free survival of 14.3 months, with iso- this side effect as manageable and thus acceptable given the ben-
lated distant recurrence as predominant pattern of failure [15]. efit of the treatment. This results interesting as we found a signif-
The pooled analysis here presented confirms these findings in a icant correlation between RN and improvement of D-PFS
larger patient collective and suggests superiority compared to his- (p = 0.047), suggesting a local immune response boosting;
166 Intraoperative radiotherapy for glioblastoma

Table 2 B.F.: Nothing to disclose.

Clinical outcomes after IORT plus standard of care. S.M.: Nothing to disclose.
Endpoint N % H.Z.: Nothing to disclose.
Progression S.Q.: Nothing to disclose.
Any progression 36 70.6 X.Q.: Nothing to disclose.
First site local 18 35.3 D.H.: Nothing to disclose.
First site distant 18 35.3 Y.A.: Reports personal fees from Carl-Zeiss Meditec, personal
No progression 15 29.4
Any local failure
fees from Merck-Serono, non-financial support from Elekta, out-
Yes 28 54.9 side the submitted work.
No 23 45.1 D.M.: Nothing to disclose.
Distant failure C.C.: Nothing to disclose.
Yes 15 29.4
F.A.G.: reports other from Implacit GmbH, non-financial support
No 36 70.6
Vital signs/cause of death from Oncare GmbH, grants and personal fees from NOXXON
Deceased 37 72.5 Pharma AG, grants and personal fees from CARL ZEISS MEDITEC
Tumor progression 21 41.2 AG, personal fees from Bristol-Myers Squibb, personal fees from
Other causes 12 23.5 Roche Pharma AG, personal fees from MSD Sharp and Dohme
Not reported 4 7.8
GmbH, personal fees from AstraZeneca GmbH, outside the submit-
Alivey 14 27.5
Salvage Therapy ted work; In addition, Dr. Giordano has a patent (US 62/435405)
Yesà 24 47.1 pending.
No 27 52.9
y
At a median follow up 18 months. Funding
à
Salvage therapies included re-surgery (n = 5 patients), re-irradiation (n = 9), other
systemic therapies (n = 18)
No funding was received for this work.

Table 3 Ethics
Incidence of radionecrosis (RN).

Radionecrosis N % Approved by the Ethics Committees of each institution, accord-

any RN 13 25.2
ing to local protocols.
Severityy
Grade I 4 7.8 Acknowledgements
Grade II 0 0
Grade III 9 17.6
Grade IV 0 0 We thank all patients and their families for their participation
Grade V 0 0 in this trial. The excellent support of the clinical trial unit shall
y
Assessed based on Common Terminology Criteria for Adverse Events (CTCAE)
be gratefully acknowledged.
version 5.0.
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