Article Comparison: Trade Publication Article and Peer Reviewed Article

Kevin Dwyer

Part I: Trade Publication

Trade publications articles are free to the public and targeted towards them. They are
written for a broad audience in a journalistic nature; informal and appealing to the reader.1
Writers of articles are usually paid for their work because of sponsorship by advertisers. This
sponsorship is also why the articles are free. I will investigate the article Radioimmunotherapy
Advancing Zevalin and Bexxar Treat Follicular B-Cell Non-Hodgkins Lymphoma written by
Arkadiy Kheyfits and published by Radiology Today. Through my investigation I will examine
relevance to medical dosimetrists (students and practicing), strength/weaknesses and the
accuracy of the information presented.
This article was something that I personally found interesting. With the emergence of
immunotherapy and new treatment modalities, I usually find myself wanting to learn more;
especially when it comes to Radioimmunotherapy (RIT). The article described two RIT drugs
that are used to treat B-cell Non-Hodgkins Lymphoma after response to normal chemotherapy
proves ineffective2. Immunotherapy uses antibodies to target cancer cells; killing them,
inactivating them or triggering an immune system response. An advantage of RIT stated by Dr.
Carrasquillo (director of targeted radiotherapy at Memorial Sloan-Kettering Cancer Center, New
York) is that patients seem to tolerate treatment with less toxic side effects than those seen with
chemotherapy. For these specific treatments, radionucleotides [Bexxar (using iodine-131) and
Zevalin (using yttrium-90)] are attached to antibodies that target the CD20 antigen found on all
mature B-cells. The radionucleotides emit Beta and Gamma radiation. Beta radiation deposits
dose in a much more localized area, whereas gamma radiation emits outside of the patient. The
benefit of Zevalin (yttrium) over Bexxar (iodine) is that Zevalin is classified as a pure Beta
emitter. A standard dose of Zevalin is given to patients whereas patients with Bexxar have to be
scanned three additional times. These and other advantages are noted in the paper, but

contraindications are missing and most of the information comes from a biased source (Dr.
Tidmarsh, chief scientific officer at Spectrum Pharmaceuticals, producer of Zevalin).
I do not believe this article is particularly helpful for practicing dosimetrists or students
at performing dosimetry. However, as students I feel we are obligated to keep up with new
technology, but always use a critical eye. Noting strengths, weaknesses and bias can be helpful
when evaluating any source of information. One weakness of this article was that it appeared to
be biased and focused on marketing Zevalin. The article only stated positive findings with
Zevalin and more importantly did not cite exact numbers or studies. The article could be more
credible if a complete list of pros and cons were covered with specific information to back up
their claims. Vague language was used including much longer timein some patients years and
years may along with other wording tricks. The study they referred to was never cited with
specific information and since most of the information came from the companys chief scientific
officer, it is hard to evaluate the information presented. On the other hand a strength the article
had was that a few of their sources were medical doctors. Also the background of RIT was
presented in a way that was easy to follow and informative for a wide group of readers.
This article provided some good information on RIT. I would recommend the first half of
this article to colleagues/classmates, but would encourage them to look at the second half with a
critical eye. The article is clearly biased towards using specifically Zevalin more frequently. The
information provided aims to persuade in favor of Zevalin over Bexxar. Light is shed less on the
advantages of RIT and more specifically the advantages of Zevalin. There are only two sources
cited and no contraindications of Zevalin or RIT are listed. I believe this article would be more
credible given specifics to support claims, wider variety of sources and more focus on the
advantages of RIT in general.

References
1. Lenards N, Weege M. Radiation Therapy and Medical Dosimetry Reading. [SoftChalk].

La Crosse, WI: UW-L Medical Dosimetry Program; 2016.

2. Kheyfits A. (2010 November). Radioimmunotherapy Advancing Zevalin and Bexxar

Treat Follicular B-Cell Non-Hodgkins Lymphoma. Radiology Today, (11)11:32.

Retrieved from http://www.radiologytoday.net/archive/rt1110p32.shtml

Part II: Peer Review

The most credible and accurate information comes from unbiased peer reviewed journal.
Professionals working within their field of expertise perform/evaluate relevant research that will
be presented to, and critiqued by their peers before publishing. Recently published journals
reference/cite existing peer-reviewed journals to build upon an existing knowledge, expand on a
theory, describe or create a new idea. The article I will critique is written by Beauchesne P, et al.
and titled A Concurrent Ultra-fractionated Radiation Therapy and Temozolomide Treatment: A
Promising Therapy for newly Diagnosed, Inoperable Glioblastoma from the International Journal
of Cancer. I will provide a brief overview and critically investigate the subsections of the article,
clarity, statistical models, potential bias and the references cited.
This journal reports on a phase II clinical trial of ultra-fractionated radiation with
concurrent chemotherapy (temozolomide) treatment for Glioblastoma (GBM). In adults, GBM is
the most common primary brain tumor, is considered one of the most radioresistant and is
subject to a high recurrence rate.1 Overall survival (OS) rate for GBM are bleak, less than 15
months. This alludes to the problem at hand; an improved treatment technique is needed. Ultrafractionated radiation entails low doses of radiation given several times a day over a course of 6
weeks. Intriguingly, an in vitro study revealed that radioresistant cells (such as glioma cells) can
exhibit a low dose hypersensitivity (HRS) to extremely low levels of radiation (<1Gy). The
article has performed and found studies that show .8 Gy three times a day has more killing power
than a single dose of 2.4 Gy. This information is found in the introduction section of the article.
It is well written and hard to stop reading. The rest of the sections are clearly labeled continuing
with the methods and materials.
Candidates for this study had to be at least 18, newly diagnosed, non-surgical candidate,
and the GBM is located in the supratentorial region (above tentorium; above hindbrain). This
study was conducted throughout eight French centers. The ultra-fractionated radiation dose of .
75 Gy was delivered to a 2.5cm margin around the GTV, 3 times per day and at least 4 hours
apart. The treatment was done 5 days a week (M-F) for 6 weeks for a cumulative dose of 67.5 Gy
over 90 fractions. Temozolomide (TMZ) was given at a dose of 75 mg/m2/day, 7 days a week
throughout the course of radiation. Following a post-radiation 4 week break, TMZ chemotherapy
resumed at 150-200 mg/m2/day for up to 6 cycles every 28 days. Patients were evaluated weekly

and a baseline exam was done at the end of radiation therapy. Patients were further evaluated
every two months until passing away.
A total of 40 patients were included in the study. The median age of the 29 men and
women was 58 years. The Kaplan-Meier statistical technique was used with 95% confidence
intervals to evaluate the OS and the progression-free survival (PFS). The trial was compared to a
2006 study that established the effectiveness of TMZ with conventional radiotherapy. Six
patients died from reasons unrelated to GBM, so only 34 patients were included in analysis. The
age range was from 29-74 years. Mathematically some of my statistics professor would not
approve the small sample size, but it depends on the size of the population of interest. In reality
and clinical practice, mathematical guidelines are not always achievable. The sample size was
not extremely large, but I believe it was sufficient for the study. Having mostly men and only
patients of French centers is not an appropriate sample of the world, but potentially can provide
insights to the potential benefits of new treatment. Complex SPSS statistical software was used
and not explained, this was hard to follow. These measurements appeared to be reliable. Some of
the results may be misleading because of the uniqueness of each patient makes variables hard to
control. The six patients who were omitted from the study may have factored into the results as
well. One interesting thing I noticed was that the 2006 TMZ/RT study that was used for
comparison had a much larger percentage of multilobal involvement (29.2%) as oppose to the
ultra-fractionation study (14.7%). Therefore a higher percentage of patients had only one lobe
involvement with the ultra-frac when compared to the 2006 study (85.3% compared to 70.9%);
this leads me to believe that more patients had a more favorable prognosis from the get-go in this
ultra-fractionation study. Despite these discrepancies the results were still interesting.
The results were adequately explained with appropriate and logically ordered section
titles. There were also tables that compared the different studies that were helpful to reference.
The statistical tests were helpful in determining that the median OS was 16 months and 8.8% of
patients were still alive. Four complete tumor responses were reported along with several partial
responses. Tumors progressed in three cases and physicians response was not followed. The
article continued to discuss how radiation therapy remains a cornerstone care for GBM. Their
reasoning flowed logically from their data and there was no bias noted. The conclusion of this
article was brief. They reported one of the longer overall survival rates for GBM non-surgical

candidates. They stated that the routine was well tolerated and a possible treatment for patients.
They further went on to say how they would like to see a study done with resected GBM
patients.
This article was well written and well researched. Almost 100 sources were cited, many
of which were quite recent and very relevant. There are many differences between this article and
the trade journal. They both are informative, but having the benefit of peer review hinders blatant
bias. The article was filled with more information, but would be more difficult for the average
reader to follow. Personally I really enjoyed this article, but had to spend a lot of time looking
into the research methods, comparing to what they cited, digging through jargon, statistical
models and other unfamiliar terms. This was a great learning experience and I look forward to
reading some more groundbreaking peer reviewed journals in the future.

References:
1. Beauchesne, P., Quillien, V., Faure, G., Bernier, V., Noel, G., Quetin, P., Gorlia, T.,
Carnin, C. and Pedeux, R. (2016), A concurrent ultra-fractionated radiation therapy and
temozolomide treatment: A promising therapy for newly diagnosed, inoperable
glioblastoma. Int. J. Cancer, 138: 15381544. doi: 10.1002/ijc.29898

Trade Journal
Radioimmunotherapy Advancing Zevalin and Bexxar Treat Follicular B-Cell Non-Hodgkins Lymphoma
By Arkadiy Kheyfits
Radiology Today
Vol. 11 No. 11 P. 32
There are two radioimmunotherapy (RIT) treatments currently approved for treatment of follicular B-cell nonHodgkins lymphoma under the brand names of Zevalin (ibritumomab tiuxetan) and Bexxar (tositumomab and iodine
I131). Both drugs operate under the same principles: Tumor cells are first targeted with a monoclonal antibody and
then are ablated by the radioactive material covalently linked to the antibody.
According to the National Cancer Institute, 65,540 new cases of non-Hodgkins lymphoma were diagnosed last year
in the United States. Eighty-five percent of non-Hodgkins lymphoma cases are of the B-cell subtype and are indolent,
but only about one half of those diagnosed will be in remission for more than five years. As reported by the American
Cancer Society, the remaining 50% will require further treatment to treat recurrent or transformed non-Hodgkins
lymphoma. Choices for treatment include external beam radiation, traditional chemotherapy, and immunotherapy, but
there are limits to each.
With external beam radiation, large radiation doses often cannot be directed to the tumor site due to the diffuse
nature of non-Hodgkins lymphoma. Chemotherapy is heavily cytotoxic, and lymphoma can develop resistance to
chemotherapy after only a few courses. Immunotherapy, which utilizes man-made antigens to target cancer cells to
either kill them or activate the bodys immune system, is a relatively new technology. Over the past decade, RIT,
which links radioactive isotopes to antigens created to bind to a receptor on the cell surface of B cells, has been
developed as a targeted option for treating diffuse disease.
Both Bexxar and Zevalin target the CD20 antigen found on all mature B cells, but a key difference is the radioactive
material found in each drug. Bexxar contains iodine-131, a beta and gamma particle emitting substance. B particles
are capable of short-range tissue destruction because they are of low path length but relatively high mass, while
gamma particles do not cause local damage because of their long path length and high energy, which directs them
out of the body. Indeed, gamma-radiation accounts for the majority of radiographic imaging.
In contrast, Zevalin contains yttrium-90 (Y-90), a pure B emitter. A key practical difference between the two
radionuclides relates to radiation safety. George Tidmarsh, MD, PhD, a pediatric oncologist and chief scientific officer
at Spectrum Pharmaceuticals, producer of Zevalin, notes that the gamma emission of its Y-90 is advantageous.
With Bexxar, much of the energy is deposited outside the body, Tidmarsh says. There are significant posttreatment
precautions for patients, such as oftentimes not being able to sleep in the same room as their spouse or loved ones
or having to carefully dispose of any clothing contaminated with radioactivity. The need for precaution does not exist
with yttrium since much of the radiation is deposited directly in the tumor and not outside the body.
Patient Selection
Before RIT can be administered, there is a careful patient selection process, according to Jorge Carrasquillo, MD, a
nuclear medicine physician and director of targeted radiotherapy at Memorial Sloan-Kettering Cancer Center in New
York City.
The current guidelines include patients that have failed other therapies, Carrasquillo says. Patients also have to be
sufficiently healthy to tolerate the treatment. Patients need to have low bone marrow involvement and a platelet count
high enough to tolerate the cytopenic effect of the treatment.
The reduced blood count that follows RIT treatment is delayed in comparison with common chemotherapy. Tidmarsh
adds that with standard chemotherapy, the time at which the lowest blood counts occur tend to be anywhere from
seven to 14 days after the administration of the chemotherapy, with recovery typically by about three weeks. With
RIT, the time to the lowest blood count takes several weeks, and recovery may take eight to 10 weeks.

Patients eligible for RIT are then referred to either a nuclear medicine specialist or a radiation oncologist familiar with
RIT. Treatment planning requires imaging to ensure correct dosimetry and confirm normal biodistribution of the
pharmaceutical.
Tidmarsh clarifies the differences between treatment with Bexxar vs. Zevalin: [Patients treated with Zevalin] are
given a standard dose of Y-90, whereas with Bexxar, the treatment is individualized depending upon how fast the
patient eliminates the radioactivity from the body. Treatment with Zevalin requires only a single whole-body scan,
with Zevalin tagged with Indium-111 instead of Y-90 to determine biodistribution. The dosimetry is then based upon
platelet count and body weight.
Carrasquillo explains that Bexxar requires three sets of scans taken over a week: one on the day of injection,
another at three to four days, and a final one after six or seven days. Dosimetry calculations are performed by a
medical physicist and then checked. Multiple scans are required to determine the effective half-life of the drug once it
is injected into the body.
After diagnostic scanning, patients are given radiation safety instructions to follow, any questions are answered,
and then the cold antibody is infused followed by the hot infusion of the drug using an infusion pump over 20 minutes.
We keep the patient for an hour for observation and then the patient is free to leave, Carrasquillo says.
Patients tolerate the treatment very well, he adds. I think the toxicity is less than seen with chemotherapy
regimens.
Both Carrasquillo and Tidmarsh agree that RIT has clinically proven efficacy. The data has shown that those patients
experience profound tumor shrinkage when treated with Zevalin, Tidmarsh says. In some cases, there is a complete
remission of the tumor, and those responseselimination of detectable evidence of diseasein some patients lasts
for a very long timeyears and years. Tidmarsh adds that he is referring to patients who have failed previous
chemotherapy treatments and are turning to Zevalin as a result.
New Indication
In the past few years, an important new indication has been FDA approved for Zevalin use. As of September 2009,
Zevalin is approved for use as a consolidation therapy, immediately following a course of chemotherapy, as a first-line
treatment for follicular B-cell non-Hodgkins lymphoma. The approval is the result of a large randomized study
presented at last years American Society of Hematology annual meeting called the First-line Indolent Trial (FIT).
Patients with follicular lymphoma were randomized to receive chemotherapy in a traditional format, Tidmarsh says.
All patients were treated with six cycles of traditional chemotherapy to eliminate as much of the disease as possible,
and those patients not showing progression during those six cycles but had shown some benefit were observed or
treated with Zevalin. The study showed that those who were treated with Zevalin on top of their initial first-line
chemotherapy experienced a much longer period of time until their lymphoma progressed to the point where
treatment was again required.
Carrasquillo believes the FIT trial will lead to a more widespread use of Zevalin but notes that there are obstacles that
block the path. An article by Schaefer and colleagues [reported on] surveys to physicians regarding RIT, he says.
The results indicated that the majority of physicians had a favorable view of RIT, but when asked why these tests
were rarely ordered, some responded that RIT wasnt available in many nuclear medicine departments, presumably
because of the high cost of the procedure resulted in fear of lack of adequate reimbursement. Other concerns
included fear by the oncologists that patients would be lost to them if they were referred elsewhere. Related to that,
oncologists have multiple drug regimens that can be used with this disease that are effective, though perhaps not as
effective as RIT, and they tend to rely on what is tried and to them true rather than RIT.
Carrasquillo believes the remedy for the concerns expressed in the article is making RIT more available in nuclear
medicine departments and enhanced education of referring physicians regarding the benefits of using Zevalin as an
adjunct therapy with traditional chemotherapy.
Tidmarsh is hopeful that with the new indication, Zevalin consolidation therapy can supersede the current standard of
care.
I could see a day in which we look at the comparison of whats normally done for newly diagnosed lymphoma
patients, which is typically chemotherapy followed by infusion every eight weeks for two years of rituxomab,
Tidmarsh says. We currently lack a randomized study, but I predict that such a study would find the outcome with

Zevalin is at least as good as with rituxomab maintenance therapy without the substantial side effects of the current
regimen. And I think what well find is that there will be a significant benefit to the patient as well as the overall
healthcare system in terms of cost; giving a single dose of Zevalin right after up-front chemotherapy is cost-effective
vs. the ongoing injections of rituxomab. If the data collection to prove cost-effectiveness is soon forthcoming, we may
see a notable change in the way newly diagnosed lymphoma is managed.
Arkadiy Kheyfits is a freelance writer based in Brooklyn, N.Y
- See more at: http://www.radiologytoday.net/archive/rt1110p32.shtml#sthash.ozxtoIGr.dpuf

Peer Reviewed

Keywords:

glioblastoma-inoperable;

low doses-radiation therapy;

ultra-fractionated regimen

Abstract
We report on a phase II clinical trial to determine the effect of a concurrent ultra-fractionated radiotherapy and
temozolomide treatment in inoperable glioblastoma patients. A phase II study opened; patients over 18 years of age
who were able to give informed consent and had been histologically proven, newly diagnosed inoperable diagnosed
and supratentorial glioblastoma were eligible. Three doses of 0.75 Gy spaced apart by at least 4 hr were delivered
daily, 5 days a week for six consecutive weeks for a total of 67.5 Gy. Chemotherapy was administered during the
same period, which consisted of temozolomide given at a dose of 75 mg/m2 for 7 days a week. After a 4-week break,
chemotherapy was resumed for up to six cycles of adjuvant temozolomide treatment, given every 28 days, according
to the standard 5-day regimen. Tolerance and toxicity were the primary endpoints; survival and progression-free
survival were the secondary endpoints. In total, 40 patients were enrolled in this study, 29 men and 11 women. The
median age was 58 years, and the median Karnofsky performance status was 80. The concomitant ultra-fractionated
radiotherapy and temozolomide treatment was well tolerated. Complete responses were seen in four patients, and
partial responses were reported in seven patients. The median survival from the initial diagnosis was 16 months.
Several long-term survivors were noted. Concurrent ultra-fractionated radiation therapy and temozolomide treatment
are well accepted by the patients. The results showed encouraging survival rates for these unfavorable patients.
Glioblastoma (GBM) is the most common primary brain tumor in adults and is characterized by a high rate of local
recurrences because of its intrinsic radioresistance.[1-4] Indeed, GBM is considered one of the most radioresistant
tumors.[1-4] After maximal surgical tumor resection as safe as possible, the current standard of care is based on a
phase III randomized trial from the EORTC/NCIC.[1-5] This treatment comprises a concurrent combination of
conformational brain radiotherapy (RT) and chemotherapy using temozolomide (TMZ), followed by a 4-week break
and adjuvant chemotherapy with TMZ for up to six cycles.[1-5] Despite the improvement in outcome with the new
standard regimen, the median overall survival (OS) does not exceed 15 months; therefore, new therapeutic strategies
are needed.[1-5]
Conformational RT remains the backbone of care for GBM. Although RT is not a curative treatment for GBM, it results
in a longer survival rate and optimized quality of life.[6] It is unclear whether clinical radioresistance in GBM is a result
of intrinsic resistance at the cellular level. The mechanisms involved in radiation resistance in mammalian cells are
more complex than once believed.[7] In vitro studies have shown that some human tumor cell lines are sensitive to

low radiation doses of <1 Gy, a phenomenon that has been termed low-dose hypersensitivity (HRS).[8-17] Strikingly,
this radiosensitivity is more apparent in radioresistant cell lines, such as glioma cells.[8-17] We demonstrated this
phenomenon in a number of various human malignant glioma cell lines using a common clinical device for irradiation.
[7, 17] Daily repeated irradiation of cells with low doses compared with irradiation with a single biologically equivalent
dose resulted in significantly higher cell death (using a clonogenic assay).[7, 17] Experiments conducted on glioma
xenografts revealed that repeated irradiation with low doses (0.8 Gy, three times a day) is more effective than a single
dose (2 or 2.4 Gy, once a day) in inhibiting tumor growth.[7, 17]
Consequently, in 2003, we began a phase II study testing an ultra-fractionated RT for inoperable de novo GBM.
[18] The results were promising, and are comparable with the results using the TMZ/RT treatment from the
EORTC/NCIC trial. However, in the ultra-fractionated RT trial, there were only a few long-term survivors that was
unexpected as these types of patients have an unfavorable prognosis (a survival expected at least 10 months), the
rate of 2-year survival was 15.48%.[18] These data suggested that the combination of ultra-fractionated radiation
therapy and concomitant and adjuvant TMZ chemotherapy (combination radiotherapy and chemotherapy is the
standard) should be more efficient. Here, we report the results of a second phase II trial that tested a concurrent
combination of ultra-fractionated brain irradiation (three-daily dosesfive times a week for six consecutive weeks)
and TMZ treatment followed by adjuvant TMZ therapy in de novo inoperable GBM patients.

Material and Methods

Patients
This phase II study was conducted in eight French centers. Patients were eligible for the study if they were at least 18
years old and had newly diagnosed, inoperable supratentorial GBM (based on neurosurgical criteria such as Rolando
and/or callosum corpus or deep locations of tumor) that was histologically confirmed (astrocytoma grade IV according
to the WHO classification). Additional inclusion criteria were a WHO performance status of 02; adequate
hematologic, hepatic and renal function; acceptable blood coagulation levels and ability to give informed consent.
Patients who had undergone a partial or complete tumor resection were not eligible.

Treatment
The RT regimen consisted of ultra-fractionated focal irradiation, with three daily doses of 0.75 Gy delivered at least 4
hr apart. Irradiation of the tumors was performed 5 days a week (Monday through Friday) for six consecutive weeks,
resulting in 90 fractions and a total of 67.5 Gy of radiation. Irradiation was delivered to the gross tumor volume with a
2.5 cm margin for the clinical target volume. RT was planned with dedicated computed tomography or magnetic
resonance imaging (MRI) and three-dimensional planning systems; conformal ultra-fractionated RT was delivered
with linear accelerators with a nominal energy 6 MeV. The patients were treated with thermoplastic immobilization
masks to ensure adequate immobilization and reproducibility. Chemotherapy consisted of TMZ treatment at a dose of

75 mg/m2/day, given 7 days a week during the ultra-fractionated RT. After a 4-week break, TMZ chemotherapy was
resumed at 150200 mg/m2/day, for up to six cycles every 28 days, in accordance with the EORTC trial.

Patient evaluation
Patients were assessed weekly for tolerance and toxicity during the RT. The baseline examination included a cranial
MRI (with and without contrast), physical and neurologic examinations, Mini-Mental-Status score (MMS) and a quality
of life questionnaire (EORTCQLQ-C30, Brain Cancer Module BN-20). A baseline examination was performed at the
end of the RT regimen (within the first 10 days after completion of the ultra-fractionated irradiation) and then every 2
months until death. The first MRI (at the end of RT) was the baseline imaging used to evaluate the tumor response,
keeping in mind that RT artifacts could be present and should be considered in the interpretation of the MRI. Tumor
progression was defined according to the modified WHO criteria (Macdonald criteria) as a 25% increase in tumor size
(size of the product of the largest perpendicular diameters of the contrast-enhanced tumor), the appearance of new
lesions or an increased need for corticosteroids.[19] When tumor progression was found, patients were treated at the
investigator's discretion, and the type of subsequent therapy (usually chemotherapy) was recorded.

MGMT analysis
DNA was extracted from FFPE samples, directly followed by bisulfite conversion using the EpiTect Fast Bisulfite
Conversion Kit. Pyrosequencing was performed with the PyroMark Q96 MGMT kit on a PSQTM96 MA system, as
previously described.[20] All the reagents were from Qiagen, Courtaboeuf, France. For data analysis, the average
percentage of the five CpGs was determined and the cutoff set at 8%.[20]

Statistical methods
The primary end points of the study were to document the treatment-related toxicity and tolerance of all patients
treated with this novel regimen. The secondary end points were the progression-free survival (PFS) and OS reported
as an intent-to-treat analysis on all 40 patients included. Survival times were calculated from the date of the initial
diagnosis (date of stereotactic biopsy) to the date of death, progression or last follow-up. The KaplanMeier
technique was used to compute the estimates for PFS and OS parameters and their 95% confidence intervals (CIs).
SPSS statistical software (SPSS, SAS Institute, Inc.) was used for the primary analyses. SAS v 9.1.3 (SAS Institute)
was the statistical software used by the EORTC for the survival analyses. To estimate the efficacy of the ultrafractionationed therapy (TEMOFRAC) on patients, we compared our results with the subgroup of patients that
underwent only a biopsy and who were treated within the EORTC/NCIC 2698122981/CE.3 trial. This randomized
trial established the combination of standard RT and concomitant treatment and maintenance with temozolomide
chemotherapy (TMZ/RT) compared with once daily fractionated RT alone. A KaplanMeier curve, log-rank test and
Cox regression were used at an exploratory 5% significance to assess the effects of TEMOFRAC compared with RT
or TMZ/RT, with and without adjustment for possible confounding effects. Available factors were age and WHO
performance status. MMSE scores were collected in only about half of the patients and were not included. MGMT
data were missing in 91% of the cases for each arm of EORTC/NCIC trial. Adjusted hazard ratios (HRs) were

computed with 95% CI. Survival analyses were performed in the intent-to-treat population. p-Values in figures are
from unadjusted analyses, and adjusted values are given in the text.

Results
Patient characteristics
From July 2008 until July 2011, 40 patients were enrolled in this phase II study; there were 29 males and 11 females.
Five patients were diagnosed with multifocal GBM. Three sudden deaths (probably due to pulmonary embolism or
myocardial infarction) and three deaths unrelated to GBM (two pulmonary infections and one grade 4 hematological
toxicity with severe sepsis) were reported in our series, so, 34 patients were finally included for the analysis (Table 1).
The median age of the population was 59 years, and ranged from 29.1 to 73.5, 14 patients were aged from >50 to
60, 18 were >60 and 10 were 70 years. Twenty-six patients had a performance status of 1, and 14 patients had a
performance status of 2.
Treatment

RT (N=45)

TMZ/RT (N=48)

TEMOFRAC (N=34)

N (%)

N (%)

N (%)

45 (100.0)

48 (100.0)

34 (100)

Female

12 (26.7)

19 (39.6)

10 (29.4)

Male

33 (73.3)

29 (60.4)

24 (70.6)

Unmethylated

2 (4.4)

3 (6.3)

11 (32.4)

Methylated

2 (4.4)

1 (2.1)

12 (35.3)

Missing

41 (91.1)

44 (91.7)

11 (32.4)

Extent of surgery: Biopsy

Sex

MGMT

Performance status

Treatment

RT (N=45)

TMZ/RT (N=48)

TEMOFRAC (N=34)

N (%)

N (%)

N (%)

Extent of surgery: Biopsy

45 (100.0)

48 (100.0)

34 (100)

14 (31.1)

17 (35.4)

4 (11.8)

24 (53.3)

22 (45.8)

18 (52.9)

7 (15.6)

9 (18.8)

12 (35.3)

50

0 (0.0)

2 (4.2)

1 (2.9)

>50 and 60

32 (71.1)

24 (50.0)

18 (52.9)

>60

13 (28.9)

22 (45.8)

15 (44.1)

Median

56.0

59.0

59.0

Age (years)

Range

41.069.0

30.070.0

29.173.5

Tumor location

One lobe

29 (64.8)

34 (70.9)

29 (85.3)

Multilobal

12 (26.7)

14 (29.2)

5 (14.7)

Other/Missing

4 (8.8)

0 (0.0)

0 (0.0)

Treatment

RT (N=45)

TMZ/RT (N=48)

TEMOFRAC (N=34)

N (%)

N (%)

N (%)

45 (100.0)

48 (100.0)

34 (100)

No

0 (0.0)

2 (4.2)

3 (8.8)

Yes

45 (100.0)

46 (95.8)

31 (91.2)

Alive

2 (4.4)

2 (4.2)

3 (8.8)

Dead

43 (95.6)

46 (95.8)

31 (91.2)

Extent of surgery: Biopsy

PFS event

Survival status

Table 1. Patient's characteristics and survival status

Treatment delivery safety and tolerability

All the 40 patients underwent and completed the ultra-fractionated irradiation and TMZ treatment. No disruptions in
the concomitant chemotherapy were reported. The treatment was delivered on an inpatient basis, 5 days of
hospitalization per week for six consecutive weeks. Although this ultra-fractionated irradiation could have cause side
effects, this regimen was well tolerated by the patients. The most common adverse event was fatigue, which is
usually noted in standard cranial RT. The main adverse effects reported were as follows:

Fatigue, grade II in 30 patients,

Alopecia, grade II in 20 patients,

Skin reaction, grade I in ten patients,

Headache, grade I in six patients,

Nausea and seizures were not reported

TMZ was administered concomitantly in all of the patients, and adjuvant chemotherapy (six cycles of TMZ) was
completed in 26 patients (76.4%). Two patients developed a pulmonary infection and one patient presented grade 4
hematological toxicity; these were all fatal (Table 2).
Type of toxicity

Number of patients

Percentage

Fatigue grade II

30

88

Alopecia grade II

20

58

Skin reaction grade I

10

29

Headaches grade I

17

Pulmonary infection grade IV

Hematological toxicity grade IV

Table 2. Toxicities reported during the phase II trial

MGMT status
The MGMT promoter analysis was only performed in 23 patients; the data were missing in the remaining 11 cases.
The MGMT promoter was found methylated in 12 of the patients (52.2%) and unmethylated in the last 11 patients
(47.8%). Because of some data missing (32%), no statistical analysis was allowed. In the case of the EORTC/NCIC
trial, MGMT data were documented in <10% of the cases. However, we noted a high rate of longer OS within the
patients with a methylation of MGMT promoter (eight of 12 patients with MGMT methylated had an OS 19 months).

Efficacy outcomes
The median follow-up of this trial was 4 years. Three of the patients are currently still alive (8.8%), and 31 patients are
dead (91.2%). The median OS was 16 months (15.92; 95% CI 9.722.6) in the analyzed population; the 2-year
survival rate was 32.4% (95% CI 17.648.0%), the 3-year 17.2% (95% CI 6.731.6%) and the 4-year rate was 9.2%
(95% CI 2.023.3%). The median PFS was 9.6 months (95% CI 7.212.12), and the PFS rate at 6 months was
76.5% (95% CI 2.023.3%). The tumor response was analyzed; four complete responses were reported, and seven
partial responses were noted. Three patients progressed during the irradiation schedule. The quality of life
questionnaire (EORTCQLQ-C30, Brain Cancer Module BN-20) was completed by only a minority of the patients;
therefore, we did not pursue any further analysis. When tumor progression was observed, the patients were treated

at the physician's discretion. The response to salvage therapy was not recorded, but an association, including
bevacizumab agent, was diffusely used.

Comparison with the EORTC/NCIC trial

We compared our results with those obtained during the EORTC/NCIC trial on patients who only had a biopsy. The
RT arm included 45 patients, the TMZ/RT arm had 48 patients and the TEMOFRAC group from this study included 34
patients. The median and 2-year OS for the RT arm and the RT/TMZ arm of the EORTC/NCIC trial were 8.7 months
(95% CI 6.311.0) and 4.6% (95% CI 0.813.7%) and 10.2 months (95% CI 7.314.1) and 10.4% (95% CI 3.8
20.9%), respectively (Tables 3 and 4). The median PFS in the RT group and RT/TMZ group was 5.0 (95% 3.25.9)
and 6.0 (95% CI 5.08.8%) months, respectively.
Survival time

Treatme Patients

Observed events Hazard ratio

p-Value (log-

Median (95% CI)

% at 2 year(s)

nt

(N)

(O)

(95% CI)

rank)

(months)

(95% CI)

RT

45

43

1.00

0.0007

8.67 (6.31, 10.97)

4.60 (0.84, 13.74

34

30

0.44 (0.27, 0.72)

TEMOFR
AC

15.92 (9.69, 22.60)

32.35 (17.62,
48.02)

Table 3. TEMOFRAC versus EORTC/NCIC RT OS

Paramet
er

Treatmen
t

DF

Parameter

Standard

estimate

error

0.47940

Chi-SquarePr>ChiSq

Hazard

95% Hazard ratio confidenc

ratio

limits

0.13000

13.5997

0.0002

0.619

0.480

0.799

WHO PS

0.18214

0.18955

0.9234

0.3366

1.200

0.827

1.740

AGE

0.02304

0.01360

2.8709

0.0902

1.023

0.996

1.051

Survival time

Treatm

Patients

Observed events Hazard ratio

p-Value (log-

Median (95% CI)

% at 2 Year(s)

ent

(N)

(O)

(95% CI)

rank)

(months)

(95% CI)

TMZ/RT

48

45

1.00

0.0364

10.23 (7.26, 14.06)

10.42 (3.82, 20.8

34

30

0.61 (0.38, 0.97)

TEMOFR
AC

15.92 (9.69, 22.60)

32.35 (17.62,
48.02)

Table 4. TEMOFRAC versus EORTC/NCIC TMZ/RT OS

Paramet
er

Treatmen

DF

Parameter

Standard

estimate

error

Chi-SquarePr>ChiSq

Hazard

95% Hazard ratio confidenc

ratio

limits

0.56821

0.24101

5.5584

0.0184

0.567

0.353

0.909

WHO PS

0.30856

0.17058

3.2721

0.0705

1.361

0.975

1.902

AGE

0.00822

0.01297

0.4021

0.5260

1.008

0.983

1.034

TEMOFRAC versus EORTC/NCIC RT: In the PFS and OS analyses, TEMOFRAC showed a

significant difference for an improved outcome over EORTC/NCIC RT (adjusted PFS: p<0.0001, HR 0.46;
95% CI 0.340.61 and adjusted OS: p=0.0002, HR 0.62; 95% CI 0.480.80) (Fig. 1).

Figure 1. PFS during the EORTC/NCIC RT and RT/TMZ vs TEMOFRAC trials.

TEMOFRAC versus EORTC/NCIC RT/TMZ: Again, an improvement in the outcome for PFS and

OS was reported for TEMOFRACversus RT/TMZ (adjusted PFS: p=0.047, HR 0.62; 95% CI 0.390.99 and
adjusted OS: p=0.0184, HR 0.57; 95% CI 0.350.91) (Fig.2).

Figure 2. Overall Survival during the EORTC/NCIC RT and RT/TMZ vs TEMOFRAC trials.

Discussion

RT remains the standard of care for GBM and has an undisputed major benefit on survival.[5, 21-23] Currently,
concomitant and adjuvant TMZ chemotherapy during RT is the standard of care for adult GBM patients aged up to 70
years and in good general and neurological condition; however, the OS for unresected GBM (biopsy) remains low,
approximately 10 months.[5] Despite their high inherent radioresistance and survival fraction at 2 Gy, GBM tumors
receive the same dose per fraction, similar total dose and equivalent overall duration of RT as others tumors
considered less radiosensitive, such as breast tumors.[21-23] In the past decade, many drugs have been developed
to improve the outcome of GBM patients, but novel approaches to the RT regimen have been ignored, except for the
development of the ballistic and intensity-modulation radiation therapy techniques (IMRT).[21-24] In the past,
alternative regimens of radiotherapy utilizing fractionation were proposed based on the hypothesis that radiation
therapy could be improved by increasing total dose or decreasing overall time of treatment.[25-30] These regimens
are called hyperfractionation (the dose per fraction is decreased, the number of fractions increased, the total dose is
increased and the total treatment time remains similar to conventional therapy time) or accelerated fractionation
schedules (the total dose and dose per fraction remain unchanged, but the number of fractions per day is increased
and thus the overall treatment time is reduced and treatment intensity increased). Hyperfractionation exploits the
difference in fractionation sensitivity between tumors and normal tissues manifesting late morbidity. In contrast,
accelerated fractionations attempt to reduce tumor proliferation as a major cause of radiotherapy failure.[25-30] A few
hyperfractionated or accelerated regimens of RT were tested on GBM patients, but all of the studies failed to
demonstrate any improvement in the OS rate, and moreover, some neurological toxicity was reported.[25-30]
Our previous studies, especially the in vitro ones, showed that daily repeated low-dose irradiation of cells, compared
to a single biologically equivalent dose, resulted in significantly higher cell death.[7, 17] Experiments conducted on
glioma xenografts demonstrated that repeated low-dose irradiation was more effective for inhibiting tumor growth
than a single large dose.[7, 17] The exact mechanisms underlying HRS are not clear. The demonstration of marked
HRS in some human radioresistant tumors suggests that inducible repair might be an important component of the
radioresistance that is apparent in these tumors at high doses. Radioresistance may only occur when there is enough
initial damage or accumulated damage to trigger DNA repair mechanisms, which are more efficient than the
constitutive DNA maintenance functions. Therefore, so-called induced radioresistance may occur only after relatively
large doses but not at doses below a certain threshold.
This low-dose hypersensitivity (HRS) phenomenon appeared to provide a new promising and effective treatment for
GBM patients; clinical trials were performed to confirm its benefit.[7, 17] Our first clinical study (ULTRA-RT), which
tested ultra-fractionated RT in de novo, inoperable GBM patients showed that this regimen was safe and well
tolerated.[18] However, the OS was only 9.53 months, which is comparable with the survival rate reported in the
literature for these unresectable GBM.[18] Interestingly, an increased number of long survivors was reported (2-year
survival was 15.48%).[18] TEMOFRAC is the first trial to explore the effects of a combined fractionated low-dose
radiation therapy and TMZ as a first-line treatment for inoperable, de novo GBM patients. The expected low-dose
hypersensitivity was observed after the ultra-fractionated RT and TMZ treatments, and an additive effect was
suggested. The TEMOFRAC clinical trial confirmed that fractionated low-dose RT is feasible, can be performed daily

and is well accepted by patients. However, this ultra fractionated regimen could be feel by the patient as more binding
that the standard treatment, for a little gain of survival.
It is noteworthy that four complete responses and seven partial responses were reported in our series; to the best of
our knowledge, this type of response has never been reported with RT for GBM patients.[1-6, 21-23] Moreover, TMZ
used in conjunction with RT and as an adjuvant regimen did not show a similar range of responses.[5, 24] Therefore,
the combination of ultra-fractionated RT and TMZ could explain this unusual high rate of response rate in our study.
Unfortunately, the toxicity in our trial was higher than expected and similar to that reported with concomitant RT and
TMZ treatment in the literature; two fatal pulmonary infections and a grade 4 hematological toxicity with a major
sepsis also fatal. At the beginning of the study, prophylactic treatment for pneumocystis lung infection was not
recommended; the absence of prophylaxis could explain the two fatal pulmonary infections. Although the
hematological toxicity from the TMZ was considered moderate, it can be severe.[5, 24] The unusual toxicity reported
in our series suggested that ultra-fraction regimen plus TMZ is not as safe as expected for this type of combination of
therapies.[5, 24] The dose per fraction is correlated to the tolerance to RT as reported in our previous ULTRA-RT
clinical trial ULTRA-RT, neurological symptomatology evoking a post-RT leukoencephalopathy was not recorded.
The results obtained for this group of GBM patients with unfavorable prognoses (biopsy only, class RPA V, some
patients >70 years old) are both surprising and promising. Taking into account our trial was a phase II study with only
34 patients and did not have a predictive factor such as MGMT status, our results displayed one of the longer OS
rates reported for inoperable GBM patients. Moreover, they are better than those noted in EORTC/NCIC trial for
unresected GBM patients.[5] The high rate of long-term survivors reported in the TEMOFRAC (32.4% 2-year survival
and 17.2% 3-year survival) confirms the efficacy of this new regimen of RT.[5, 24] GBM is a highly vascularized tumor
that overexpresses vascular endothelial growth factor A (VEGF-A), a key regulator of tumor-associated angiogenesis.
[23] Previous results from clinical trials support a role for the anti-VEGF-A molecule bevacizumab in recurrent and
newly diagnosed GBM.[31] Two large phase III studies have recently been published that evaluated bevacizumab
treatment in conjunction with RT and concomitant and adjuvant TMZ treatment as the first-line treatment for GBM
(AVAGLIO and RTOG 0825).[32, 33] Both trials showed a 34 month prolongation of the PFS with bevacizumab but
without significant effects on the OS (AVAGLIO OS was 16.8 months in the bevacizumab arm and 16.7 months in the
control arm; RTOG 0825 OS was 15.7 months in the bevacizumab group and 16.1 months in the control group). It is
noteworthy that only 10% of patients underwent a stereotactic biopsy in the AVAGLIO trial; at least 3% underwent one
in the RTOG study.[32, 33] TEMAVIR, a French phase II randomized trial, was conducted to evaluate bevacizumab
and irinotecan as neoadjuvant and adjuvant treatments combined with TMZ chemoradiation for unresectable GBM;
there were no differences found in the two arms for survival (OS was 11.1 months).[31] Our results are significantly
better than those from the TEMAVIR trial, and are comparable with those obtained from the AVAGLIO and RTOG
0825 trials.[31-33]
In conclusion, this trial reported one of the longer OS rates for unresectable GBM, and the regimen is feasible for
routine clinical practice, and well accepted by the patients. The combination of ultra-fractionated RT and TMZ given
concomitantly and in an adjuvant schedule merits further evaluation especially in resected GBM patients.

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