Accelerated hyperfractionation plus temozolomide in glioblastoma

Abstract

Introduction:
Hyperfractionated (HFRT) or accelerated hyperfractionated radiotherapy (AHFRT) have been discussed as a potential treatment for glioblastoma based on a hypothesized reduction of late radiation injury and prevention of repopulation. HFRT and AHFRT have been examined extensively in the pre-Temozolomide era with inconclusive results. In this study we examined the role of accelerated hyperfractionation in the Temozolomide era.

Materials and methods:
Sixty-four patients who underwent AHFRT (62 of which received Temozolomide) were compared to 67 patients who underwent normofractionated radiotherapy (NFRT) (64 of which received TMZ) between 02/2009 and 10/2014. Follow-up data were analyzed until 01/2015.

Results:
Median progression-free survival (PFS) was 6 months for the entire cohort. For patients treated with NFRT median PFS was 7 months, for patients treated with AHFRT median PFS was 6 months. Median overall survival (OS) was 13 months for all patients. For patients treated with NFRT median OS was 15 months, for patients treated with AHFRT median OS was 10 months. The fractionation regimen was not a predictor of PFS or OS in univariable- or multivariable analysis. There was no difference in acute toxicity profiles between the two treatment groups.

Conclusions:
Univariable and multivariable analysis did not show significant differences between NFRT and AHFRT fractionation regimens in terms of PFS or OS. The benefits are immanent: the regimen does significantly shorten hospitalization time in a patient collective with highly impaired life expectancy. We propose that the role of AHFRT + TMZ should be further examined in future prospective trials.

Full text

R E S E A R C H Open Access
Accelerated hyperfractionation plus
temozolomide in glioblastoma
David Kaul
*†
, Julian Florange
†
, Harun Badakhshi, Arne Grün, Pirus Ghadjar, Sebastian Exner and Volker Budach
Abstract
Introduction: Hyperfractionated (HFRT) or accelerated hyperfractionated radiotherapy (AHFRT) have been discussed
as a potential treatment for glioblastoma based on a hypothesized reduction of late radiation injury and prevention
of repopulation. HFRT and AHFRT have been examined extensively in the pre-Temozolomide era with inconclusive
results. In this study we examined the role of accelerated hyperfractionation in the Temozolomide era.
Materials and methods: Sixty-four patients who underwent AHFRT (62 of which received Temozolomide) were
compared to 67 patients who underwent normofractionated radiotherapy (NFRT) (64 of which received TMZ)
between 02/2009 and 10/2014. Follow-up data were analyzed until 01/2015.
Results: Median progression-free survival (PFS) was 6 months for the entire cohort. For patients treated with NFRT
median PFS was 7 months, for patients treated with AHFRT median PFS was 6 months. Median overall survival (OS)
was 13 months for all patients. For patients treated with NFRT median OS was 15 months, for patients treated with
AHFRT median OS was 10 months. The fractionation regimen was not a predictor of PFS or OS in univariable- or
multivariable analysis. There was no difference in acute toxicity profiles between the two treatment groups.
Conclusions: Univariable and multivariable analysis did not show significant differences between NFRT and AHFRT
fractionation regimens in terms of PFS or OS. The benefits are immanent: the regimen does significantly shorten
hospitalization time in a patient collective with highly impaired life expectancy. We propose that the role of
AHFRT + TMZ should be further examined in future prospective trials.
Introduction
Gliomas are the most common primary tumors of the
central nervous system (CNS) in adults representing about
one third of central nervous system tumors and 81 % of
all malignant CNS tumors reported in the United States
[1]. The most common and most malignant type of glioma
is glioblastoma (GBM), with a median overall survival
(OS) rate of 15 months after surgical resection followed by
adjuvant radiotherapy (RT) and Temozolomide (TMZ)
chemotherapy. The prevalence of GBM is highest in pa-
tients aged 50 years or older and is likely to increase with
the ongoing demographic shift toward older ages [2].
Well-known postitive prognostic factors for OS in GBM
patients are young age at diagnosis, high Karnofsky
performance score (KPS), great extent of neurosurgical
resection, O-6-methylguanine-DNA methyltransferase- gene
(MGMT) methylation as well as isocitrate dehydrogenase
(IDH) 1-mutational status [3–5]. Current standard of care
for newly diagnosed GBM comprises maximal safe resec-
tion, adjuvant radiotherapy with (RT) with concurrent TMZ
and post-RT TMZ chemotherapy [6, 7]. Fractionated RT to
the tumor bed in 30 fractions of 2 Gy in single doses of
2 Gy to a total accumulated dose of 60 Gy delivered over
the course of 6 weeks has been widely accepted as the
standard fractionation regimen, balancing effectiveness with
radiation toxicity. Recently some authors have suggested
hypofractionated regimens for the elderly and frail patient
population [8, 9] other authors have evaluated the role of
hypofractionation plus TMZ [10].
Other authors have examined the potential role of
hyperfractionated- (HFRT) and accelerated hyperfractio-
nated radiotherapy (AHFRT) as well as the role of protons
in GBM [11]. The use of HFRT and AHFRT is based on a
hypothesized reduction of late radiation injury and pre-
vention of tumor repopulation in treatment intervals [12].
* Correspondence: david.kaul@charite.de
†
Equal contributors
Klinik für Radioonkologie und Strahlentherapie, Charité Universitätsmedizin
Berlin, Campus Virchow-Klinikum, Augustenburger Platz 1, 13353 Berlin,
Germany
© 2016 Kaul et al. 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.
Kaul et al. Radiation Oncology (2016) 11:70
DOI 10.1186/s13014-016-0645-3
Content courtesy of Springer Nature, terms of use apply. Rights reserved.

Despite plausible rationales, various trials have failed
to prove the superiority of dose-escalated HFRT and
AHFRT in the pre-TMZ era [13].
In 1994, the European Organization for the Research and
Treatment of Cancer (EORTC) reported an AHFRT dose
escalation trial using doses of 42–60 Gy in 2 Gy fractions
three times daily, which failed to show differences in survival
in all groups. No additional chemotherapy was used [13]. In
1999 Lutterbach et. al. showed survival rates for 1.5 Gy
thricedailyto54GycomparabletoconventionalRT,again
no chemotherapy was used [14]. In 2001 Prados et. al.
showed data for AHFRT with or without difluromethylor-
nithine (DFMO) vs. conventional irradiation with or without
DFMO with no OS benefit for the experimental groups [15].
The RTOG 83–02 study tested HFRT (2 × 1.2 Gy to
doses of 64.8, 72, 76.8, or 81.6 Gy) vs. AHFRT (2 ×1.6 Gy
to doses of 48 or 54.4 Gy), all groups received concurrent
bis-chloroethyl (BCNU). Contrary to the other aforemen-
tioned studies HFRT patients who had received higher
doses of 76.8 and 81.6 Gy showed superior survival com-
pared to the AHFRT groups [16].
In summary, the data on HFRT and AHFRT mainly
stem from the pre-TMZ era and are not fully conclusive.
We therefore want to present experience from our insti-
tution on the treatment of patients with newly diagnosed
GBM with AHFRT of 2 × 1.6 Gy to 59,2 Gy and concurrent
and sequential Temozolomide following the Stupp regimen.
Apart from a potential reduction of tumor repopulation as
well as a hypothesized reduced late toxicity rate, the regi-
men does significantly shorten hospitalization time in a
group of patients with highly impaired life expectancy.
Materials and methods
Treatment decisions, patient selection and dose regimens
Starting from 01/2009 patients with resected GBM with
organs-at-risk (OAR) in close proximity to the resection
cavity were offered adjuvant radio-chemotherapy (RCTx)
with single doses of 1.6 Gy twice daily to a total dose of
59.2 Gy (19 days schedule) as an alternative to a conven-
tional fractionation with single doses of 2 Gy up to 60 Gy
(30 days schedule, NFRT). Of 131 patients 126 received
continuous daily TMZ (75 mg per square meter of body-
surface area per day, 7 days per week from the first to the
last day of radiotherapy), followed by six cycles of adjuvant
TMZ (150 mg per square meter for 5 days during each
28-day cycle).
In this study we carried out a retrospective analysis of 64
patients who underwent AHFRT plus TMZ and compared
them with 67 patients who underwent NFRT plus TMZ be-
tween 02/2009 and 10/2014. Follow-up data were analyzed
until 01/2015.
In our institution treatment decisions are based on the
votes of an interdisciplinary tumor board. Usually all
patients <70 years with a KPS >50 % are offered adjuvant
AHFRT + TMZ or NFRT + TMZ. AHFRT + TMZ is of-
fered when OARs such as the optic nerves, chiasm or
brainstem would be touched by the CTV and covered by
the PTV, and in case that the patient is willing and fit
enough to undergo treatment twice daily.
Patients ≥70 yeas of age either receive hypofractionated
radiotherapy or TMZ only (depending on MGMT-status).
Stratification, variables and follow-up
Patients were stratified according to fractionation scheme,
age, gender, KPS, extent of surgery (biopsy, partial-, gross
total resection), MGMT-status, tumor localization (frontal,
parietal, temporal, occipital, central) and planning target
volume (PTV). Follow-up examinations, including MRI as
well as clinical and neurologic examinations were per-
formed at 6–8 week intervals after radiotherapy.
Treatment planning
Target delineation in GBM varies substantially between dif-
ferent institutions and several consensus statements are
available. However, an ESTRO-ACROP guideline is avail-
able since January 2016 [17]. Adjuvant RCTx was initiated
within 4 weeks after surgical resection or stereotactic bi-
opsy. Contrast agent enhanced computed tomography in a
thermoplastic mask as well as gadolinium enhanced mag-
netic resonance imaging (MRI) was performed before RT
planning.
Target volumes were based on preoperative and postop-
erative MRI. The gross tumor volume (GTV) was defined
as the summation of the postoperative surgical cavity with
or without residual tumor lesion(s) as well as tumor exten-
sion on the preoperative T1-weighted gadolinium-
enhanced imaging. The diffusion-weighted imaging (DWI)
images were also used in the estimation of GTV. The ex-
tent of peritumoral edema was not routinely included in
the clinical target volume (CTV), however, an all-round
GTV margin of 2 cm was mandatory. For the planning tar-
get volume (PTV) an additional 0.5 cm margin was added.
Intensity-modulated radiation therapy (IMRT) was applied
using a 6-MV linear accelerator with multileaf collimators.
Until 2012 treatment was performed using step-and-shoot
intensity-modulated radiation therapy (IMRT), starting in
early 2012 all patients were treated using volumetric arc
therapy (VMAT).
Toxicity
Higher grade acute toxicity (≥3°) was analyzed for 90 days
post treatment according to CTCAE 4.0.
Formulas and statistics
Overall survival (OS) and progression-free survival
(PFS) were calculated from the first day of irradiation
Kaul et al. Radiation Oncology (2016) 11:70 Page 2 of 7
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using Kaplan-Meier analysis and the log-rank test.
Progression was defined retrospectively by clinical
note assessments that included integration of imaging
and clinical status. Subgroups were compared using uni-
variable analysis and the Cox proportional hazard model
for multivariable analysis. A p-value of less than 0.05 was
considered statistically significant. A p-value of less than 0.1
was considered a trend. All variables from the univariable
analysis were included in multivariable analysis. All statis-
tical analyses were performed using IBM SPSS Statistics 19
(New York, USA).
Results
Patient characteristics
Patient characteristics are shown in Table 1. One hun-
dred thirty-one patients treated for GBM were identified
in our retrospective analysis. Sixty-seven were treated
with NFRT and 64 patients were treated using AHFRT.
The two groups were well matched in terms of gender,
PTV, tumor localization, MGMT-status, extent of sur-
gery, KPS and TMZ treatment and salvage treatment.
Median age in the AHFRT group was lower than in the
NFRT group (p< 0.001).
Table 1 Patient characteristics of the 131 GBM patients analyzed
Overall Collective NFRT AHFRT p-value
(n= 131) (n= 67) (n= 64)
Median Age (min/max) [y] 61 12/80 63 43/78 59 12/80 p< 0.001 (*)
Mean PTV ± sd [ccm] 355 ±142 339 ±141.4 373 ±141.8 p= 0.17
n% n%n%
Gender m 88 67.2 % 46 68.7 % 42 65.6 % p= 0.85
f 43 32.8 % 21 31.3 % 22 34.4 %
Localization Frontal 42 32.1 % 16 23.9 % 26 40.6 % p= 0.38
Parietal 31 23.7 % 17 25.4 % 14 21.9 %
Temporal 38 29.0 % 22 32.8 % 16 25.0 %
Occipital 9 6.9 % 4 6.0 % 5 7.8 %
Central 9 6.9 % 6 9.0 % 3 4.7 %
n/a 2 1.5 % 2 3.0 % 0 0.0 %
MGMT-status unmethylated 63 48.1 % 32 47.8 % 31 48.4 % p= 0.66
methylated 43 32.8 % 23 34.3 % 20 31.3 %
n/a 25 19.1 % 12 17.9 % 13 20.3 %
Extent of surgery Biopsy 16 12.2 % 6 9.0 % 10 15.6 % p= 0.38
Partial resection 57 43.5 % 28 41.8 % 29 45.3 %
Gross tumor resection 51 38.9 % 29 43.3 % 22 34.4 %
n/a 7 5.3 % 4 6.0 % 3 4.7 %
KPS 50 % 7 5.3 % 4 6 % 3 4.7 % p= 0.3
60 % 49 37.4 % 27 40 % 22 34.4 %
70 % 47 35.9 % 24 36 % 23 35.9 %
80 % 28 21.4 % 12 18 % 16 25.0 %
Temozolomide yes 126 96.2 % 65 97.0 % 61 95.3 % p= 0.68
no 5 3.8 % 2 3.0 % 3 4.7 %
Salvage treatment Re-irradiation 20 15.3 % 12 17.9 % 8 12.5 %
Chemotherapy (tmz) 45 34.4 % 24 35.8 % 21 32.8 %
Chemotherapy (other) 6 4.6 % 3 4.5 % 3 4.7 %
Bevacizumab 11 8.4 % 5 7.5 % 6 9.4 %
Imatinib 1 0.8 % 0 0.0 % 1 1.6 %
Dendritic cell vaccination 1 0.8 % 1 1.5 % 0 0.0 %
NFRT normofractionated radiotherapy, AHFRT accelerated hyperfractionated radiotherapy, PTV planning target volume, n/a not applicable, MGMT O-6-methylguanine-DNA
methyltransferase, KPS Karnofsky performance status, tmz temozolomide
Kaul et al. Radiation Oncology (2016) 11:70 Page 3 of 7
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Progression-free survival
Median PFS was 6 months for the entire cohort (Table 2).
For patients treated with NFRT median PFS was 7 months,
for patients treated with AHFRT median PFS was
6 months. At 6 months PFS was 56.9 % in the NFRT
group and 51.7 % in the AHFRT group. At 12 months PFS
was 16.9 % in the NFRT group and 19 % in the AHFRT
group, (Fig. 1). There was no difference between both dose
regimens in univariable analysis (p=0.95).
Overall survival
Of 131 patients analyzed 107 had died at the time of
analysis (01/2015).
Median OS was 13 months for all patients (Table 3).
For patients treated with NFRT median OS was
15 months, for patients treated with AHFRT median OS
was 10 months. At 12 months OS was 66 % in the NFRT
group and 48.2 % in the AHFRT group. At 24 months
OS was 14.7 % in the NFRT group and 16.7 % in the
AHFRT group (Fig. 2). There was no difference between
both dose regimens in univariable analysis (p= 0.46).
Prognostic factors
Positive predictors of survival in univariable analysis were
female gender, higher KPS, MGMT methylation and gross
total resection. In multivariable analysis MGMT methyla-
tion and gross total resection remained significant
Table 2 Univariable analysis of potential preditive factors of progression-free survival
Univariable analysis Multivariable analysis
Variable HR 95 % CI pMedian PFS [m] HR 95 % CI p
Age (< vs. > = median of 61 years) 1.08 0.75–1.55 0.69 6 vs. 6 –– –
Gender (m vs. f) 0.68 0.46–1.01 0.05 6 vs. 9 0.57 0.35–0.92 0.022 (*)
KPS (< vs. > = median of 70 %) 0.5 0.34–0.72 <0.001 (*) 4 vs. 9 0.5 0.33–0.78 0.002 (*)
MGMT-status (methylated vs. unmethylated) 1.46 0.97–2.2 0.07 9 vs. 6 1.61 1.03–2.52 0.036 (*)
Localization (other vs. central) 1.51 0.76–3 0.24 6 vs. 5 –– –
PTV (< vs. > = median of 337 ccm) 1.13 0.79–1.62 0.51 7 vs. 6 –– –
Subtotal resection or biopsy vs. gross total resection 0.71 0.49–1.02 0.07 4 vs. 8 –– –
Fractionation regimen (NFRT vs. AHFRT) 1.01 0.95–1.01 0.95 7 vs. 6 –– –
(*) p-value ≤0.05, HR hazard ratio, CI confidence interval, PFS progression-free survival, KPS Karnofsky performance status, MGMT O-6-methylguanine-DNA methyl-
transferase, PTV planning target volume, NFRT normofractionated radiotherapy, AHFRT accelerated hyperfractionated radiotherapy
Fig. 1 Kaplan-Meier analysis of PFS rates grouped according to dose regimen. No significant differences were found between both groups
Kaul et al. Radiation Oncology (2016) 11:70 Page 4 of 7
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predictors, the factor “smaller PTV”became significant in
multivariable analysis. Gender and lower KPS were not
significant in multivariable analysis.
The fractionation regimen was not a predictor of
survival in univariable- or multivariable analysis.
Subgroup analysis according to predictive factors did
not reveal any specific group to benefit from either NFRT
compared to AHFRT or vice versa (Table 4).
Toxicity
All patients in both groups completed radiotherapy. All pa-
tients scheduled for concurrent chemotherapy (126/131)
completed concurrent TMZ. In the normofractionated
group seven patients did not complete post-radiotherapy
TMZ due to neutropenia or thrombocytopenia. In the
hyperfractionated group 3 patients did not complete post-
radiotherapy TMZ due to neutropenia or
thrombocytopenia.
There was no difference in acute toxicity profiles
between the two treatment groups. There were seven
grade 3 and six grade 4 events in the normofractio-
nated group (grade 3 events: 1 × headache, 2 × neuro-
logical, 3 × neutropenia, 1 × thrombocytopenia. Grade
4 events: 2 × neutropenia and 4 × thrombocytopenia).
Fig. 2 Kaplan-Meier analysis of OS rates grouped according to dose regimen. No significant differences were found between both groups
Table 3 Univariable analysis of potential preditive factors of overall survival
Univariable analysis Multivariable analysis
Variable HR 95 % CI pMedian OS [m] HR 95 % CI p
Age (< vs. > = median of 61 years) 1.18 0.8–1.7 0.4 14 vs. 12 –– –
Gender (m vs. f) 0.62 0.4–0.95 0.028 (*) 11 vs. 16 0.64 0.38–1.08 0.095
KPS (< vs. > = median of 70 %) 0.96 0.94–0.98 <0.001 (*) 9 vs. 15 –– –
MGMT-status (methylated vs. unmethylated) 1.68 1.08–2.61 0.021 (*) 16 vs. 11 1.89 1.158–3.09 0.011 (*)
Localization (other vs. central) 1.71 0.83–3.56 0.15 13 vs. 13 –– –
PTV (< vs. > = median of 337 ccm) 1.37 0.93–2.02 0.11 14 vs. 12 1.61 1–2.6 0.048 (*)
Subtotal resection or biopsy vs. gross total resection 0.64 0.43–0.95 0.025 (*) 11 vs. 15 0.62 0.39–0.98 0.041 (*)
Fractionation regimen (NFRT vs. AHFRT) 1.16 0.79–1.71 0.46 15 vs. 10 –– –
(*) p-value ≤0.05, HR hazard ratio, CI confidence interval, OS overall survival, KPS Karnofsky performance status, MGMT O-6-methylguanine-DNA methyltransferase,
PTV planning target volume, NFRT normofractionated radiotherapy, AHFRT accelerated hyperfractionated radiotherapy
Kaul et al. Radiation Oncology (2016) 11:70 Page 5 of 7
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In the hyperfractionated group there were two grade 3
events and six grade 4 events (grade 3 events: 1 × neuro-
logical, 1 × nausea/vomiting. Grade 4 events: 3 × neutro-
penia, 3 × thrombocytopenia).
Discussion
Survival
Most studies on hyperfractionation and accelerated
hyperfractionation stem from the pre-TMZ era, com-
parabilityofPFSandOSratesisthuslimited.Inour
study median OS was 13 months for all patients, 15 months
for patients treated using NFRT and 10 months for patients
treated with AHFRT. Univariable and multivariable analysis
did not show significant differences between the fraction-
ation regimens. This is worthwile to know, because an
AHFRT-regimen with 3.5 weeks overall treatment time was
capable to equalize the OS-results of the classical 6 weeks
treatment. Bearing in mind the limited prognosis of these
patients the dose-intensified treatment is a clear benefit.
One of the first studies on AHFRT in GBM was pub-
lished in 1994 by González et al. who used doses of
42–60 Gy in 2 Gy fractions three times a day. Median
survival was 8.7 ± 0.7 months and no statistically significant
differences were found for the four different dose-level
groups [13].
Lutterbach et. al. published median OS rates of 8.8 months
for 1.5 Gy thrice daily to 54 Gy [14].
In 2001 Prados et al. published survival rates of pa-
tients treated with AHFRT ± DFMO vs. conventional
irradiation ± DFMO with no OS benefit for the experi-
mental groups (8.6–9.8 months) [15].
Werner et al. published the RTOG 83–02 data in
1996, patients received HFRT (2 × 1.2 Gy to doses of
64.8, 72, 76.8, or 81.6 Gy) vs. AHFRT (2 ×1.6 Gy to
doses of 48 or 54.4 Gy), all groups received concurrent
BCNU. Contrary to the other aforementioned studies
HFRT patients who had received higher doses of 76.8
and 81.6 Gy showed superior survival compared to the
AHFRT groups. The authors found median OS rates be-
tween 10.8 and 12.7 months [16].
In 2005 Stupp et al. published data demonstrating a
survival benefit for GBM patients that received concur-
rent Temozolomide with postoperative radiation, with
median survival of 14.6 months for patients receiving
concurrent therapy versus 12.1 months for patients
who received only radiotherapy [7]. This treatment has
since become the standard of care for primary GBM
and is referred to as the “Stupp regimen”in everyday
clinical routine.
OS rates for all patients of 13 months as shown here
are comparable to the data published by Stupp et al. and
we did not find significant differences in OS between
AHFRT and NFRT in our patient collective.
Limitations
Our study had several limitations. Firstly, the two groups
analyzed were not perfectly matched in terms of age.
Secondly, the MGMT-status is unknown in approximately
20 % of patients in both treatment groups. Thirdly, no
analysis of chronic toxicity was performed due to the in-
trinsic uncertainties of retrospective analysis. Fourthly, the
number of patients analyzed here in both groups might
simply be too low to find significant differences in survival
between the both regimens. Fifthly, patients with GBM in
close proximity to the brainstem were more likely to re-
ceive AHFRT, potentially biasing OS rates.
Conclusions
The role of AHFRT in the TMZ era remains unclear.
The potential benefits are a reduction of tumor repopu-
lation as well as reduced late toxicity. Other benefits are
immanent; the regimen does significantly shorten
hospitalization time in a patient collective with highly im-
paired life expectancy. We propose that the role of AHFRT
+ TMZ should be further examined in future prospective
trials.
Competing interests
The authors declare that they have no competing interests.
Table 4 Subgroup analysis of potential preditive factors of
overall survival did not identify any specific subgroup to benefit
from either NFRT compared to AHFRT or vice versa
Median OS [m]
NFRT AHFRT p
Variable
Age < median of 61 years 15 12 0.66
> = median of 61 years 15 9 0.28
Gender m 14 9 0.31
f 16 14 0.98
KPS < median of 70 % 12 6 0.16
> = median of 70 % 15 13 0.67
MGMT-status methylated 16 15 0.73
unmethylated 14 9 0.09
Localization other 15 10 0.41
central 9 17 0.44
PTV < median of 337 ccm 15 12 0.82
> = median of 337 ccm 15 9 0.24
Extent of resection Subtotal resection or biopsy 13 8 0.14
gross total resection 15 13 0.6
KPS Karnofsky performance status, MGMT O-6-methylguanine-DNA
methyltransferase, PTV planning target volume, NFRT normofractionated
radiotherapy, AHFRT accelerated hyperfractionated radiotherapy
Kaul et al. Radiation Oncology (2016) 11:70 Page 6 of 7
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Authors’contributions
DK drafted the manuscript, performed statistical analysis and supervised the
discussion of the manuscript. JF helped drafting the manuscript, collected
data and helped with statistical analysis. HB planned the study and took part
in the discussion of the manuscript. AG, PG and SB took part in the
discussion of the manuscript. VB planned the study and helped drafting the
manuscript. All authors approved the final version of this manuscript.
Received: 11 February 2016 Accepted: 10 May 2016
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