北海道脳神経疾患研究所医誌第21巻

2010．12．P75〜79

Gamma Knife Radiosurgery for Recurrent Glioblastoma Resistance tothe Temozolomide
Ken-ichi SATO, M.D., Tamio ITO, M.D., Masami TAKANASHI, M.D., Yoshimaru OZAKI, M.D.,
Mitsuteru OIKAWA, M.D., Yoshinori SUGIO, M.D. and Hirohiko NAKAMURA, M.D.
Department of Neurosurgery, Brain Tumor Center, Gamma Knife Center, Nakamura Memorial Hospital andHokkaido Brain Research Foundation, Sapporo, Japan
Abstract:
Purpose: The current standard of care for newly diagnosed glioblastoma is surgical resection to the extent feasible,
followed by radiotherapy plus concomitant and adjuvant temozolomide. Ultimately despite this current standard
treatment, almost all patients with glioblastoma will have relapse.
Gamma knife stereotactic radiosurgery (GK-SRS) is a safe and less invasive treatment used as adjuvant therapy
for patients with glioblastoma. Several studies have yielded conflicting results in the effectiveness of radiosurgeryin glioblastoma. This article describes the results of our institutional experience with GK-SRS adjuvant therapy inthe treatment of patients with recurrent glioblastoma resistance to the temozolomide.
Method: Twenty-six patients with newly diagnosed glioblastoma were treated with operation and concomitant temozolomide radio-chemotherapy from 2006 to 2010. Eleven patients with recurrent glioblastoma were treated withGK. Seven patients were male and 4 were female. The median age at primary diagnosis of the tumor was 64.8
years (range, 51-81 yrs). All patients were received debulking surgery. Histology evaluations of all patients
revealed glioblastoma. In all patients radiotherapy was performed as first-line therapy, applied as fractionatedexternal beam radiotherapy with concomitant temozolomide chemotherapy. The median interval between initialdiagnosis and primary GK was 9.0 months (range, 4-17 mos). The median target tumor size was 8.4 cm3 (range,0.65-38.8 cm3). The median dose applied was 17.5 Gy (range, 15-20 Gy) prescribed to the 53.5% (range, 45-95%) isodose line that encompassed the target volume. The median follow-up time was 19.6 months (range, 11-48 months).
Result: Median survival time of patients treated with GK was 21.0 months and without GK was 14.0 months.
Treatment was well tolerated by all patients. Acute toxicities CTCAE Grade II occurred in one patient. Conclusion:
Gamma knife radiosurgery is a relative safe and less invasive treatment and may play an important role in thetreatment of recurrent glioblastoma resistance to the temozolomide.
Keyword: glioblastoma, Gamma knife radiosurgery, temozolomide−75−Purpose
The current standard of care for newly diagnosed
glioblastoma multiforme (GBM) is surgical resection
to the extent feasible, followed by radiotherapy plus
concomitant and adjuvant temozolomide1). Ultimately despite this current standard treatment, almost all
patients with GBM will have relapse.
Gamma knife stereotactic radiosurgery (GK-SRS) isa safe and less invasive treatment used as adjuvant
therapy for patients with GBM. Several studies haveyielded conflicting results in the effectiveness ofradiosurgery in GBM. This article describes theresults of our institutional experience with GK-SRS
adjuvant therapy in the treatment of patients withrecurrent GBM resistance to the temozolomide.
Patients and Methods
Study Population
Twenty-six patients with newly diagnosed GBM
were treated with operation and concomitant temozolomide radio-chemotherapy from 2006 to 2010.
Eleven patients with recurrent GBM were treatedwith GK-SRS. Seven patients were male and 4 werefemale. The median age at primary diagnosis of thetumor was 64.8 years (range, 51-81 years). All
patients were received debulking surgery. Histology

evaluations of all patients revealed GBM. In all
patients radiotherapy was performed as first-line
therapy, applied as fractionated external beam radiotherapy (EBRT) with concomitant temozolomidechemotherapy (Table 1).
The criteria used for GK-SRS treatment included:
1) Histopathological diagnosis of GBM at tumor
resection2) Tumor lesion smaller than 30 cm3 in size3) Karnofsky performance score (KPS) greater than604) Life expectancy greater than 3 months
GK-SRS Treatment Protocol
Treatment doses were prescribed to the 50% isodose
line that encompassed the 5 mm margin to the contrast-enhancing tumors in patients with recurrent
tumors. The median target tumor volume was 8.4
cm3 (range, 0.65-38.8 cm3). The median treatment
dose was 17.5 Gy (range, 15-20 Gy) prescribed to the53.5% (range, 45-80%) isodose line, which corresponds
to a maximal GK-SRS dose was 33,8 Gy (range, 30-40Gy).
Statistical Methods
Patients were routinely followed every 8 to 12 weeks
from completion of EBRT or GK-SRS until their timeof death. The median follow-up time was 19.6 months(range, 11-48 months). The median interval between
initial diagnosis and primary GK-SRS was 8.4
months (range, 6-17 months). Survival was analyzed
using Kaplan-Meier method. In addition to overall
survival from the time of diagnosis was analyzed.
ResultMedian survival time of patients treated with GKSRS was 21.0 months and without GK-SRS was 14.0
months (Fig. 1). Treatment was well tolerated by all
patients. Acute toxicities CTCAE Grade II occurred in
one patient.

Table 1 Patient and treatment characteristics−76−

Fig. 1 Overall survival
Discussion
Appearance of temozolomide seemed whether could
put light in treatment of GBM, a lot of patients with
GBM did not responded to the temozolomide, even if
the standard therapy that uses temozolomide wasdone2), the median survival was only 14.6 months1).
In the extension of the survival time of GBM, theadjuvant therapy becomes important when leading torecurrence after operation and concomitant temozolomide radio-chemotherapy. Molecular target therapy3)
and cell immunotherapy4) are tried as new treatment
to GBM in temozolomide resistance, but it's the clinical test stage and there is no adaptation of healthinsurance by the current state.
GK-SRS is the treatment which applies a gamma
ray of high dose to stereotaxically to a small lesion
basically, it has been thought that the treatment
about the tumor that shows permeated growth is difficult. However, GK-SRS may be enumerated in oneof the choices of the adjuvant therapy in the point oflimited part controlling a tumor of a certain period aswell as the further surgery for a small recurrent
tumor after it is removed by the operation all5).
In uncontrolled trials, several investigations havepreviously demonstrated encouraging data withimproved survival of patients with GBM after additional adjuvant therapy with GK-SRS. The results ofseveral series investigating the survival benefit ofGK-SRS for patients with GBM. In, 1997, Kondzilka,et al. 6) reported a median overall survival of 26

months in 64 patients with GBM with a mean tumor
volume of 6.5 cm3.
However, most recently the Radiation Therapy
Oncology Group (RTOG) concluded the 93-05 Phase-3
trial with 203 patients randomized to receive GK-SRS
followed by radiation therapy plus bischloroethylnitrosourea (BCNU) versus only radiation therapy plus
BCNU and reported no difference in survival in thetwo arms7). They reported a median survival of 13.7
months versus 14.1 months, and concluded by a resultof this RCT, it seemed that GK-SRS was denied as
standard treatment of GBM which remains clearly
after an operation.
But Hsieh8) reported that a median survival when
GK-SRS was performed at the time of recurrence
after early stage treatment in 26 examples of glioblastoma was 16.7 months while a median survival when
GK-SRS was performed after early stage treatment in
25 examples of glioblastoma was 10 months. The
importance of the timing of GK-SRS as effectivenessand the adjuvant therapy was emphasized.
By the results of our institutional experience withGK-SRS adjuvant therapy in the treatment ofpatients with recurrent glioblastoma resistance to thetemozolomide, the median survival was 21 months.
These results exceed a report of Hsieh, but influenceof improvement of the effect of temozolomide and theextraction rate by the first time operation is considered.
As the merit of GK-SRS to recurrent GBM, (1) It's
low invasive compared with a re-operation. (2) It's
possible to treat more than one times. (3) A treatment
period is short (by the hospitalization which is 3 days
2 nights, in an irradiation time, from 30, 60 minutes).
(4) It's mentioned that health insurance is adaptationin Japan.
In case of recurrent tumor of in the pyramidal tract
neighborhood, and a re-operation are performed, apossibility of the motor paralysis after an operation ishigh. But extension in a living period at home isobtained without KPS decreasing after it treats, preventing invasion with a recurrence tumor to a pyramidal tract by GK-SRS (Gamma defense) (Fig. 2).
As the weak point, the local control of the recurrent
tumor by GK-SRS is completely impossible. Recurrence including dissemination from the irradiation
outdoors is seen by the majority.

−77−Fig. 2 Gamma defense: Protection of the pyramidal tract
This consideration, retrospective selection bias wasconsideration, not randomized controlled trial, andhad as of the adaptation of GK-SRS when recurring,and moreover it wasn‘t significant in statistical way
by the patient who did GK-SRS and the patient who
didn't do GK-SRS. When recurring, the median survival by the good case in the state relatively withadaptation of GK-SRS is the conclusion that it was 21months. Though the locality control of the tumor was
temporarily possible by GK-SRS, there was a casefrom whom the limited part control became fatal by adifficult example and dissemination finally, and it
was thought the limit of the GK-SRS by the current
state.
To improve treatment results with GK-SRS forrecurrent glioblastoma, setting in an irradiation areaand reconsideration of the treatment dose are needed.
GBM characteristically infiltrates surrounding normal brain parenchyma with malignant cells that canbe identified up to 4 cm from the tumor edge9). Whenbuilding a dosimeter picture to recurrent GBM, theirradiation target was encompassed the 5 mm‐1 cm
margin to the contrast-enhancing tumors. But recurrence from 2 cm in the range of an irradiation partwas insufficient as much local control. Because PET
is used when the range of the irradiation target of
GBM is decided, the setting of an effective range ofthe irradiation target is biologically expected (However, PET that uses 11C-methionine is now outside theadjustment of medical insurance in Japan).
The median treatment dose was 17.5 Gy prescribedto the 50% isodose line) a maximal dose was 33.8 Gy(range, 30-40 Gy). It is thought that the increase ofthe treatment dose is possible when it is based thatthe acute radiation damage of CTCAE Grade II wasonly one patient taken as an adverse experience. It
could be thought that rational irradiation target
using PET and increase of the treatment dose wasnecessary it was based on this treatment results, andto improve local control of a recurrent GBM.
For the irradiation volume to become large for irradiation to a recurrence tumor around the tumor
extraction cavity of wide range, such a case to be able
to do nothing but decrease the therapeutic dose isthought that the irradiation divided into several-timeby a low dose is necessary.
The timing of treatment is important to improvetreatment results in GK-SRS for recurrent GBM. An
average period from a check to GK-SRS in the firsttime was 8.4 months by this consideration. A tumor
is regarded as the time to tend to recur this time.
When treating a recurrence tumor with GK-SRS, it isthought that it is related to the improvement of treatment results to treat smaller lesion by a wide range
and a high dose. When doing GK-SRS in a recurrent
GBM, it is important to treat GK-SRS from the diagnosis first time about 8 months while it is recognizedtime when the relapse is caused easily, doesn't overlook a small relapse, and the recurrent lesion is small.
It is necessary to understand the role and the meaning of each treatment method including not only asingle treatment method but also the initial treatment and the adjuvant therapy well, and to set up thetreatment strategy the collection academically for
GBM. Ascertaining the merit of the GK-SRS and theweak point and treating as one of the combinedmodality therapies are important.
Conclusion
Gamma knife radiosurgery is a relative safe and lessinvasive treatment and may play an important role in
the treatment of recurrent glioblastoma resistance tothe temozolomide.
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