From: Subject: Stereotactic radiosurgery for glioblastoma: retrospective analysis Date: Sun, 12 Apr 2009 10:43:57 +0200 MIME-Version: 1.0 Content-Type: multipart/related; type="text/html"; boundary="----=_NextPart_000_0000_01C9BB5B.956AEB00" X-MimeOLE: Produced By Microsoft MimeOLE V6.00.2900.5579 This is a multi-part message in MIME format. ------=_NextPart_000_0000_01C9BB5B.956AEB00 Content-Type: text/html; charset="utf-8" Content-Transfer-Encoding: quoted-printable Content-Location: http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=19292912 =EF=BB=BF Stereotactic radiosurgery for glioblastoma: = retrospective analysis = <= LINK=20 rel=3Dstylesheet type=3Dtext/css=20 href=3D"http://www.pubmedcentral.nih.gov/corehtml/pmc/css/pmcbars-slatebl= ue.css"><= LINK=20 rel=3Dstylesheet type=3Dtext/css=20 href=3D"http://www.pubmedcentral.nih.gov/corehtml/pmc/css/pmcrefs3.css"> =
3D"BioMed3D"Reference3DSearch.3DRegistration.3D"Journal
Journal=20 List > Radiat=20 Oncol > v.4= ;=20 2009
Abstract
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PubMed articles by:
Biswas,=20 T.
Okunieff,=20 P.
Schell,=20 M.
Milano,=20 M.
Radiat Oncol. = 2009; 4: 11.=20
Published online 2009 = March 17.=20 doi:=20 10.1186/1748-717X-4-11.
PMCID:=20 PMC2662864
Copyright<= /A>=20 =C2=A9 2009 Biswas et al; licensee BioMed Central Ltd.
Stereotactic radiosurgery for glioblastoma:=20 retrospective analysis
Tithi Biswas,1 = Paul=20 Okunieff,1 Michael C Schell,1 Therese=20 Smudzin,1 Webster H Pilcher,2 Robert S=20 Bakos,2 G Edward Vates,2 Kevin A=20 Walter,2,3 Andrew Wensel,2 David = N=20 Korones,3,4,5 and Michael T=20 Milano3D"corresponding1
1Department of Radiation Oncology, = University of Rochester Medical Center, Rochester, NY 14642, = USA
2Department of Neurosurgery, = University of=20 Rochester Medical Center, Rochester, NY 14642, USA
3Department of Medicine, Division = of=20 Oncology, University of Rochester Medical Center, Rochester, NY = 14642,=20 USA
4Department of Pediatrics, = University of=20 Rochester Medical Center, Rochester, NY 14642, USA
5Department of Neurology, = University of=20 Rochester Medical Center, Rochester, NY 14642, USA
3D"correspondingCorresponding=20 author.
Tithi=20 Biswas: tithi_biswas/at/urmc.rochester.edu ; Paul = Okunieff:=20 paul_okunieff/at/urmc.rochester.edu ; Michael = C Schell:=20 michael_schell/at/urmc.rochester.edu ; Therese = Smudzin:=20 tithi_biswas/at/urmc.rochester.edu ; Webster = H Pilcher:=20 webster_pilcher/at/urmc.rochester.edu ; Robert = S Bakos:=20 robert_bakos/at/urmc.rochester.edu ; G = Edward Vates:=20 edward_vates/at/urmc.rochester.edu ; Kevin A = Walter:=20 kevin_walter/at/urmc.rochester.edu ; Andrew = Wensel:=20 andrew_wensel/at/urmc.rochester.edu ; David N = Korones:=20 david_korones/at/urmc.rochester.edu ; Michael = T Milano:=20 mtmilano/at/yahoo.com
Received January 2, 2009; Accepted March = 17,=20 2009.
"=20 = src=3D"http://www.pubmedcentral.nih.gov/corehtml/pmc/pmcgifs/square.gif">= Abstract
Abstract
Purpose
This retrospective = study was done=20 to better understand the conditions for which stereotactic = radiosurgery=20 (SRS) for glioblastoma may be efficacious.
Methods
Between 2000 and 2007, = 33 patients=20 with a pathological diagnosis of glioblastoma received SRS with = the=20 Novalis=C2=AE Shaped Beam Radiosurgery system. Eighteen = patients=20 (54%) underwent salvage SRS for recurrence while 15 (45%) patients = received upfront SRS following standard fractionated RT for newly=20 diagnosed glioblastoma.
Results
There were no RTOG = grade >2=20 acute side effects. The median survival after SRS was 6.7 months = (range=20 1.4 =E2=80=93 74.7). There was no significant difference in = overall survival (from=20 the time of initial diagnosis) with respect to the timing of SRS = (p =3D=20 0.2). There was significantly better progression free survival in = patients=20 treated with SRS as consolidation versus at the time of recurrence = (p =3D=20 0.04). The majority of patients failed within or at the margin of = the SRS=20 treatment volume (21/26 evaluable for recurrence).
Conclusion
SRS is well tolerated = in the=20 treatment of glioblastoma. As there was no difference in survival = whether=20 SRS is delivered upfront or at recurrence, the treatment for each = patient=20 should be individualized. Future studies are needed to identify = patients=20 most likely to respond to SRS.
"=20 = src=3D"http://www.pubmedcentral.nih.gov/corehtml/pmc/pmcgifs/square.gif">= Introduction
Introduction
Glioblastoma is an aggressive primary brain = tumor=20 with poor outcome. Fractionated radiation therapy is the primary = adjuvant=20 treatment following resection or biopsy [1]. The addition of concurrent (with radiation) and = adjuvant=20 temozolomide has recently been shown to significantly improve = survival in=20 glioblastoma, and is now considered to be standard of care = following=20 resection [2-4]. However, the inability to adequately locally = control=20 disease, either upfront or at recurrence, continues to be a major=20 challenge for this highly infiltrative tumor.
There appears to be a dose response to = radiotherapy=20 for glioblastoma up to about 60 Gy. In late 1970s, retrospective = analyses=20 of previous randomized trials by the Brain Tumor Study Group = established a=20 dose-response between 50 =E2=80=93 60 Gy for glioblastoma [5]. Another randomized study by Medical Research = Council=20 confirmed that there is an improvement in median survival from 9 = months to=20 12 months when adjuvant radiation dose was increased from 45 Gy to = 60 Gy=20 [6]. Several prospective dose escalation trials, = some=20 utilizing hyperfractionation or accelerated fractionation regimens = have=20 suggested a possible dose response relationship for glioblastoma, = though=20 no randomized trials have shown any survival benefit over standard = fractionated 60 Gy [1,7-15]. The Radiation Therapy Oncology Group (RTOG) = conducted a=20 phase III randomized study (RTOG 93-05) for newly diagnosed = glioblastoma=20 to assess whether the addition of upfront stereotactic = radiosurgery (SRS)=20 improves patient outcome; the results suggested that an SRS boost = does not=20 significantly improve disease control or patient survival [16].
Regardless of the initial treatment, = glioblastoma=20 recurrences predominantly occur at the site of the initial tumor = [17-20]. For recurrent glioblastoma, the prognosis is = usually=20 grim. Repeat surgery when feasible and chemotherapy are often used = for=20 salvage of recurrent glioblastoma. Re-irradiation with standard=20 fractionated radiotherapy is feasible, particularly with modern = radiation=20 techniques, but often considered risky because of the cumulative = dose to a=20 large volume of normal brain structures [21]. SRS, by virtue of its improved set-up = accuracy, allows=20 for a reduction in the volume receiving the prescribed dose, and = can=20 therefore be advantageous over standard radiotherapy. The role of = SRS in=20 this setting has not been tested in a prospective randomized = study.=20 Several retrospective series have demonstrated a median survival = on the=20 order of 7=E2=80=9311 months, albeit with a of selection bias = favoring patients=20 who are amenable to SRS [22-30]. We undertook this retrospective analysis to = look at the=20 SRS dosimetry treated with Novalis Shaped Beam Radiosurgery, as = well as=20 the outcome of all treated patients.
"=20 = src=3D"http://www.pubmedcentral.nih.gov/corehtml/pmc/pmcgifs/square.gif">= Clinical=20 Materials and Methods
Clinical Materials and Methods
The University of Rochester = has been=20 treating intracranial lesions with SRS since December 1992 and has = been=20 using the Novalis Shaped Beam Surgery system with BrainLAB = planning=20 software since 2000.
The charts of 33 patients = with a=20 pathological diagnosis of glioblastoma (WHO grade IV) who = underwent SRS=20 treatment between November 2000 and April 2007 were = retrospectively=20 reviewed. The study was approved by the University of Rochester = Research=20 Subjects Review Board.
Patient Selection
Patients were selected = to be=20 amenable to SRS if their enhancing lesions were <4 cm in size. = The=20 decision for a patient to undergo SRS following fractionated = radiotherapy=20 for newly diagnosed glioblastoma was at the discretion of the = treating=20 physicians, including the radiation oncologist, medical oncologist = and the=20 neurosurgeon. The majority of patients who received upfront SRS = were=20 either treated prior to the published result of RTOG-93-05 or as = part of=20 an ongoing protocol in which SRS was allowed [31]. The decision for patients to undergo salvage = SRS was=20 also at the discretion of the treating physicians.
Radiosurgery Treatment
SRS was delivered with the Novalis linear = accelerator=20 (BrainLAB A.G., Heimstetten, Germany), equipped with = micromultileaf=20 collimators (MLC), using 6 MV photons. The tungsten MLC leaves at = the=20 center of the field are 3 mm in thickness. A BrainLAB stereotactic = head=20 frame (BrainLAB A.G., Heimstetten, Germany) was used for = immobilization=20 during the computerized tomography (CT) scan and during treatment. = A=20 Novalis localizer frame (BrainLAB A.G., Heimstetten, Germany) was = attached=20 during the CT scan. CT and magnetic resonance imaging (MRI) scans = were=20 used to delineate the target and normal structures. Lesion = enhancement=20 seen on the Gadolinium-T1 weighted MRI images were defined as GTV. = The GTV=20 was expanded by 0=E2=80=931 mm to generate the PTV. BrainLAB = planning software=20 (BrainLAB A.G., Heimstetten, Germany) was used to generate a = treatment=20 plan. The prescribed isocenter dose was generally 10=E2=80=9320 = Gy, extrapolating=20 from the RTOG protocol 90-05 guidelines in which prescribed dose = was=20 dependent upon target volume [32]. The maximum prescribed dose was based on size = of the=20 lesion and the proximity of critical structures. We generally did = not=20 prescribe the isocenter dose >20 Gy. Generally, the = =E2=89=A580% isodose line=20 covered =E2=89=A599% of the PTV. The dose constraints for critical = structures=20 were: brain stem <10 Gy; optic chiasm and optic nerves <8 = Gy; normal=20 brain (brain minus GTV) <14 Gy. All patients received 10 mg of=20 intravenous decadron prior to their SRS and were kept overnight in = the=20 hospital for observation.
Follow-up
Following SRS, all = patients were=20 followed at 6 weeks and thereafter every 2=E2=80=933 months. For = each follow-up=20 examination, every patient underwent a contrast enhanced MRI scan = and a=20 neurological evaluation. MR-spectroscopy, MRI perfusion and/or PET = imaging=20 were performed as needed to help to distinguish radiation necrosis = from=20 tumor progression.
Statistical analysis
Both overall survival = and=20 progression free survival were our endpoint analysis. Using the=20 Kaplan-Meier method, overall survival was calculated from two = different=20 time points: from the initial diagnosis and from the time of SRS.=20 Progression free survival was calculated from the time of SRS = until tumor=20 recurrence, tumor progression or death, which ever occurred first. = All=20 statistical analysis was performed using statistical software = Stata=20 9.1.
"=20 = src=3D"http://www.pubmedcentral.nih.gov/corehtml/pmc/pmcgifs/square.gif">= Results
Results
Patient Characteristics
The patient and tumor = characteristics=20 are shown in Table 1.=20 All patients had a Karnofsky performance status of =E2=89=A570. = The median age at=20 the time of diagnosis was 57.8 years (range 33=E2=80=9381 years). = All patients=20 received external beam radiation, delivered to a median dose of 60 = Gy=20 (range 50=E2=80=9364 Gy) with 1.8 =E2=80=93 2 Gy per fraction. Six = patients were treated=20 with accelerated radiation (64 Gy, 1.6 Gy twice daily) as part of = a=20 University of Rochester pilot protocol[31] Sixteen patients (48%), received temozolomide=20 concurrently during their fractionated radiotherapy, 2 patients = received=20 other concurrent chemotherapy and 15 (45%) patients received no = concurrent=20 chemotherapy. The majority of patients (85%) received adjuvant=20 chemotherapy after radiation while 15% received no adjuvant = chemotherapy.=20 Adjuvant chemotherapy included single agent temozolomide or BCNU = in most=20 patients. In a few patients, other drugs, such as irinotecan or = etoposide=20 were given in combination with BCNU or temozolomide.
Table=20 1
Patient=20 = Characteristics
A total of 18 patients underwent SRS = at=20 recurrence, 14 underwent SRS upfront as a consolidation and 1 = patient=20 underwent SRS upfront as consolidation as well as at the time of=20 recurrence (12 months after the first SRS). The latter patient, = for the=20 purpose of data analysis, was included in the group of patients = undergoing=20 upfront consolidative SRS. Another patient received two salvage = SRS=20 procedures, to the same location, for two chronologically separate = recurrences (8 months apart). In the 18 patients treated for = recurrence,=20 the median interval from diagnosis to SRS was 12.1 months (4.1 = =E2=80=93 44.4);=20 while in the other 15 patients it was 1.3 months (0.4 =E2=80=93 = 7.6). For patients=20 who received SRS at recurrence, the median interval from the = fractionated=20 to the SRS was 9.1 months (range 1.8 =E2=80=93 40.2 months).
Table 2=20 summarizes the SRS dosimetric analysis. The median dose at the = isocenter=20 was 14 Gy. The median and maximum volume for consolidative and = salvage SRS=20 were not significantly different (p =3D 0.2)
Table=20 2
Radiation = treatment=20 = parameters
One patient who received 6.4 = Gy at the=20 isocenter underwent SRS following fractionated radiotherapy for = tumor=20 progression and worsening neurological symptoms. The lesion was = located in=20 the left parietal lobe close to the motor strip and had a cystic = component=20 as well as an enhancing component of the lesion. The entire area = was=20 treated using 2 isocenters. Given the patient's worsening = neurological=20 symptoms, and close proximity of the motor strip, he was treated = with an=20 unusually low dose.
Toxicity
The RTOG toxicity criteria = were used.=20 There was no grade >2 acute toxicity. One patient developed = grade 4=20 late-toxicity. This patient was initially treated with accelerated = radiotherapy (64 Gy in twice-daily 1.6 Gy fractions) with = concurrent=20 temozolomide, followed by an SRS boost and adjuvant temozolomide. = His=20 post-SRS MRI scans at 2 and 4 months showed enlarging tumor with = altered=20 enhancement and decreased blood perfusion; magnetic resonance = spectroscopy=20 revealed a largely lipid-lactate peak and mildly elevated=20 choline-creatinine ratio at the margin. Ultimately, he underwent a = second=20 craniotomy 5 months after his SRS. The pathology revealed 80% = necrotic=20 tumor, with some viable tissue. Among the viable component, small = areas of=20 fibrosis, blood pigment and macrophages were seen along with = gemistocytic=20 and ganglionic type of cells. The p-53 was rare and there was = minimal=20 Ki-67 activity. His post-operative MRI showed no residual necrotic = tumor=20 but post-surgical changes. Unfortunately, he developed wound = complications=20 and is currently recovering from his third craniotomy.
There are 4 patients who are = long-term (>3=20 years) survivors from glioblastoma, 2 of whom have long-term = follow-up=20 after SRS. One patient is alive at 76 months from the diagnosis of = glioblastoma in the left temporal lobe, and 75 months from SRS. He = is=20 decadron dependent and suffers from neurocognitive decline, = slurred speech=20 and expressive aphasia. He was treated with upfront SRS (15 Gy) = following=20 63 Gy of fractionated radiation; he also received a short course = of=20 etoposide and >3 years of temozolomide.
A second long term survivor is alive = at 50 months=20 from SRS and 76 months from the diagnosis. She suffers short-term = memory=20 loss and psychosocial difficulty. She was treated with = fractionated=20 radiotherapy (63 Gy) and concurrent temozolomide. At her first = tumor=20 recurrence, she was treated with 9 cycles of BCNU & = irinotecan. She=20 suffered a second, PET positive, recurrence 9 months later and was = treated=20 with SRS (12 Gy). She also was given 28 months of high dose (80 = mg)=20 Tamoxifen. Another patient died at 47 months from original = diagnosis, and=20 13 months after SRS, as a result of neurocognitive decline, with = apparent=20 local control of his tumor (based on MRI follow-up). He suffered a = total=20 of 4 recurrences and was treated quite aggressively with a salvage = gross=20 total resection, as well as two separate radiosurgeries at = recurrence (20=20 and 18 Gy at the isocenter, respectively). He also received = adjuvant=20 chemotherapy with BCNU, thalidomide and temozolomide at = recurrence. In=20 these 3 patients, it is difficult to ascribe the cause of the late = treatment effect, which may or may not be attributable to=20 radiosurgery.
A fourth patient is alive at = 6 months=20 from SRS and 50 months from diagnosis with recurrent and = progressive=20 disease. He was treated with radiation (59.4 Gy) with concurrent = and=20 adjuvant temozolomide. He suffered recurrence after 2 years and = was=20 treated with bevacizumab and irinotecan initially followed by SRS = (10=20 Gy).
Outcome
The median survival from = the time of=20 initial diagnosis was 16.9 months (4.5 =E2=80=93 76.2 months). The = 1-year, 2-year=20 and 3-year overall survival rates were 72%, 23% and 14% = respectively.=20 Figure 1=20 depicts overall survival from the time of diagnosis. There was no=20 difference in survival whether patients received SRS as = consolidation or=20 at recurrence (p =3D 0.4).
Figure=20 1
Overall=20 survival from the initial=20 = diagnosis.
The median survival from the time of = SRS was 6.7=20 months (1.4 =E2=80=93 74.7 months). Figure 2=20 illustrates the survival curve from the time of SRS. The patients = who=20 received up-front SRS had a median survival of 10.3 months = compared to 5.3=20 months among those who received SRS at recurrence, although this=20 difference was not statistically significant on univariate = analysis (p =3D=20 0.1). Table 3=20 summarizes the patient survival.
Figure=20 2
Overall=20 survival from the time of stereotactic=20 = radiosurgery.
=
Table=20 3
Patient=20 Survival
The median progression free survival = from the=20 time of SRS was 4.3 months (1.3 =E2=80=93 74.7 months). On = univariate analysis,=20 patients who had SRS as consolidation had a significantly better=20 progression free survival compared to patients who received SRS at = the=20 time of recurrence (median progression free survival of 6 months = vs. 3.4=20 months, respectively, p =3D 0.04) (Figure 3).
Figure=20 3
Progression=20 free survival: upfront stereotactic radiosurgery (SRS) = versus SRS=20 for=20 recurrence.
As part of out = hypothesis-generating=20 analysis, we looked at various prognostic variables for overall = survival,=20 including age, tumor location, type of surgery, use of concurrent=20 chemotherapy, and timing of SRS. Only temporal lobe location was=20 significantly better on univariate analysis (p =3D = 0.01).
Recurrence pattern prior to = SRS
For patients (n =3D = 18) who=20 underwent SRS for recurrence, all except one have information = about their=20 recurrence pattern prior to the SRS. Nine patients (53%) failed = within the=20 previously irradiated volume, while 3 patients (17%) failed both = within=20 and at the margin of the previously irradiated volume. Three = patients=20 (17%) failed both outside and within the irradiated volume. One = patient=20 (6%) failed at the margin only and 1 patient (6%) failed only = outside the=20 previously irradiated volume.
Recurrence pattern after = SRS
Seven patients were = unable to be=20 evaluated for recurrence, due to loss of follow-up (n =3D 3) or = death prior=20 to imaging follow-up (n =3D 4). Three patients were locally = controlled at=20 last follow-up, 3 of whom are alive at 74.7, 50.4 and 4 months = after SRS,=20 and 75.4, 50.4, 7.3 months after initial diagnosis, respectively. = Among=20 the 23 patients who experienced recurrence, 21 (92%) recurred = within the=20 SRS field or at the field margin, while 1 (8%) recurred outside of = the SRS=20 field.
Salvage treatment
Information about = salvage therapy=20 at recurrence was available in 29 patients and is summarized in = Table 4.=20 Two patients had SRS for subsequent recurrences and two patients = underwent=20 surgical salvage prior to SRS. The majority of patients received = salvage=20 chemotherapy.
Table=20 4
Salvage=20 therapy
"=20 = src=3D"http://www.pubmedcentral.nih.gov/corehtml/pmc/pmcgifs/square.gif">= Discussion
Discussion
glioblastoma continues to be a challenging = disease to=20 treat, with most patients succumbing to their disease in the = course of a=20 few months to a few years. Since the late 1970s when adjuvant = radiation=20 was found to improve survival, very little progress has been made = in=20 further improving the survival. In 2005, the EORTC and NCIC = conducted a=20 phase III trial, investigating temozolomide during and after = radiation [2]; this regimen yielded a modest but significant = improvement=20 in survival for this aggressive tumor, a small impact made almost = after 25=20 years since the report by Walker et al established that 60 Gy as = the most=20 effective dose for glioblastoma from a pooled retrospective = analysis [5].
The inability to control the tumor locally, = with=20 distant brain metastases being far less common than local = recurrence, led=20 to the hypothesis that by increasing the radiation dose, local = control and=20 survival may improve. SRS is one of the methods of dose escalation = which=20 had been hypothesized to improve outcome [33,34]. The RTOG 93-05 study randomized >200 = patients with=20 glioblastoma to SRS boost in addition to 60 Gy fractionated = radiation and=20 BCNU chemotherapy; no survival benefit was appreciated with the = addition=20 of an SRS boost [16]. As size was a criterion for eligibility for = SRS boost,=20 a subsequent analysis of RTOG data found even by RPA = stratification, SRS=20 offers no significant added advantage [35]. In an attempt to further clarify the role of = SRS in=20 malignant glioma, Tsao M et al. reviewed the literature and = concluded that=20 there is level I-III evidence that the addition of an upfront SRS = boost to=20 fractionated radiation and BCNU offers no benefit to survival, = local=20 control or quality of life in malignant glioma, with a greater = risk of=20 toxicity [36]. Similar conclusions were reached in an = evidenced based=20 review in this journal, though the authors conclude that "selected = patients may benefit but the specific characteristics of this = group have=20 yet to be identified" [1].
Because a high percentage of patients = experience=20 local recurrence following standard therapy, salvage therapy is = often=20 challenging. Resection, chemotherapy or radiation are the various = options=20 which play an important role in the management of recurrent = disease [37,38]. Retrospective data, including matched pair = analyses=20 suggest that salvage therapy prolongs progression free survival = and=20 overall survival, albeit with a selection bias favoring those = patients=20 undergoing salvage [39]. Since these tumors are quite infiltrative, a = second=20 surgery is often not feasible. Fractionated re-irradiation can be = quite=20 risky because a larger volume of previously treated brain is = enclosed=20 within the radiated volume. SRS, by virtue of rigid = immobilization, allows=20 for minimal radiation dose exposure to surrounding tissue. SRS is=20 therefore well suited for patients undergoing a second course of=20 radiation, as the normally accepted dose tolerances of normal = structures=20 would otherwise likely need to be exceeded to ensure adequate = target=20 coverage. In the RTOG 93-05 study, 19% of patients randomized to = the arm=20 without upfront SRS received SRS as salvage, 6% received = fractionated=20 radiation and 35% underwent salvage surgery. In contrast, 6% of = patients=20 randomized to the arm with upfront SRS received SRS as salvage, 7% = received fractionated radiation and 33% underwent resection. = Arguably, one=20 can conclude that the RTOG 93-05 study does not necessarily show = that SRS=20 is not beneficial in patients with glioblastoma, but rather SRS = can be=20 delayed as part of salvage therapy without a detriment in = survival.
The data on=20 salvage SRS for recurrent glioblastoma is sparse and mostly = retrospective=20 making it difficult to interpret. A few retrospective studies have = examined SRS with recurrent glioblastoma; these are summarized in = the=20 Table 5.=20 The median survival after SRS is on the order of 8=E2=80=9312 = months. Late=20 toxicity other than radiation necrosis is uncommonly reported. = Among those=20 patients who undergo a neurosurgical procedure for progression = and/or=20 suspected radionecrosis, necrosis is admixed with viable tumor = cells in=20 nearly all samples. Generally, radionecrosis is reported in = roughly 5=E2=80=9310%=20 of cases,36,37 though most patients develop radiographic evidence = of=20 necrosis [40]. The number of patients who are found to have = pathologic=20 necrosis will obviously be impacted by the aggressiveness of the=20 neurosurgeon and the amenability of the tumor and patient to = surgical=20 exploration and debulking. As a consequence, the extent of = radionecrosis=20 after SRS is difficult to accurately quantify and characterize, = but=20 certainly it is not prohibitive to treatment, particularly since = tumor=20 progression is the primary means of death and diminished quality = of life=20 in most patients.
Table=20 5
Summary = or studies=20 on the use of salvage stereotactic radiosurgery for = recurrent=20 = glioblastoma
In our study, the median survival = following SRS=20 was 6.7 months which is comparable with the most reported series. = The=20 majority of the patients who received SRS as an upfront boost were = treated=20 prior to the reported results of RTOG 95-03. The median survival = from the=20 time of SRS for the up-front SRS was slightly better (10.3 months) = compared to the patients who had SRS at recurrence (5.3 months). = However,=20 the median interval between the diagnosis and SRS was 1.3 months = versus=20 12.1 months for patients who had consolidative SRS and SRS at = recurrence,=20 respectively. When we looked at the overall survival from the time = of=20 diagnosis, there is no difference in these two groups. = Interestingly, we=20 found significant improvement in progression-free survival when = SRS was=20 added as a consolidative treatment. We did not analyze the quality = of life=20 measure to see if delay in progression free survival is associated = with=20 any improvement in quality of life.
We have two long term survivors over 6 = years in each=20 group indicating it is not only the treatment but also the tumor = biology=20 which is probably crucial. As we develop greater understanding of = tumor=20 biology, we might be able to identify a subset of patients who = would=20 require more aggressive therapy compared to those who will do = better=20 without any aggressive therapy [41,42]. A recent article by Krex et al. suggested = that patients=20 who have hypermethylated MGMT protein are the long-term survivors = [42]. Hegi et al. reported from the EORTC = randomized trial=20 that those patients who had methylated MGMT gene benefited = significantly=20 better from temozolomide than the patients who did not [43]. Most of the SRS literature pre-dates the = temozolomide=20 era. Currently, whether more aggressive initial local therapy, = including=20 SRS, will have more benefit among patients receiving temozolomide, = with or=20 without the methylated MGMT gene, is unknown.
In our series, there was no RTOG = >grade 2=20 acute toxicity seen. One patient developed grade 4 late toxicity = and=20 underwent craniotomy for this. The pathology largely showed = necrosis (80%)=20 with some viable tissue including both fibrosis and tumor cells = and=20 minimal Ki-67 activity. Among our 4 long-term survivors who lived = over 4=20 years since the diagnosis of their glioblastoma, three are still = alive.=20 One patient died presumably from treatment related toxicity. = However, he=20 received aggressive surgery, multiple courses of radiation and = prolonged=20 chemotherapy and all these factors might have contributed to the = toxicity=20 rather than just radiation. The other patient who is still alive = after 6=20 years has grade 2 late toxicity.
In conclusion, SRS is = generally a well=20 tolerated treatment both as a boost and as a salvage therapy. As = there was=20 no difference in survival between the two groups, the decision of = adding=20 SRS to fractionated treatment should be based on individual = patient status=20 and preference. In the temozolomide era, the role of SRS needs to = be=20 better defined by future studies.
Competing interests
The authors declare = that they have=20 no competing interests.
Authors' contributions
TB and MM conceived = and designed=20 the study. PO, MS, WP, GEV, KW, DK and MM treated patients on the = study.=20 TB, MM and TS analyzed data. All authors participated in drafting = and=20 revising the manuscript. All authors have given final approval of = the=20 manuscript.
 
Acknowledgements
This data was = presented at the=20 2008 American College of Radiation Oncology (ACRO) meeting in = Miami,=20 Florida
"=20 = src=3D"http://www.pubmedcentral.nih.gov/corehtml/pmc/pmcgifs/square.gif">= References
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Articles=20 from Radiation Oncology = (London,=20 England) are provided here courtesy of
BioMed=20 Central
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'this' to reuse same window, else ""=0A= // windowname: Reference name for window=0A= // additional: Attributes for window.open, from:=0A= // width, height, resizable, scrollbars, toolbar, location, = directories,=0A= // status, menubar, copyhistory.=0A= // Notes: Book version always provides menubar, toolbar, etc.=0A= //=0A= function startTargetBook(link,windowname,width,height,additional)=0A= {=0A= startTarget(link,windowname,width,height,additional)=0A= }=0A= =0A= =0A= //=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D= =3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D= =3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D= =3D=3D=3D=3D=3D=0A= function startTarget(link,windowname,width,height, additional)=0A= {=0A= if(! window.focus)=0A= return;=0A= =0A= var sizestring =3D ",width=3D" + width + ",height=3D" + height;=0A= var opt =3D = "menubar=3Dno,toolbar=3Dno,status=3Dno,scrollbars=3Dyes,resizable=3Dyes,d= ependent=3Dyes,location=3Dno";=0A= var allOptions =3D opt + sizestring;=0A= if (additional) { allOptions =3D allOptions + ',' + additional; }=0A= =0A= windowname =3D String(windowname).replace(/-/g, "_")=0A= var moveToXDefault =3D 75=0A= var moveToYDefault =3D 50=0A= =0A= var moveToX =3D moveToXDefault=0A= var moveToY =3D moveToYDefault=0A= var yAdj =3D 50=0A= var yAdjDelta =3D 25=0A= =0A= var barNames =3D ['menubar', 'toolbar', 'statusbar']=0A= for (var idx in barNames)=0A= { =0A= if (String(allOptions).lastIndexOf(barNames[idx] + '=3Dyes') > =0A= String(allOptions).lastIndexOf(barNames[idx] + '=3Dno'))=0A= yAdj +=3D yAdjDelta=0A= }=0A= =0A= try {=0A= if (window.screen.width && width > 0)=0A= moveToX =3D Math.ceil((window.screen.width - width)) - 15=0A= moveToX =3D (moveToX > 0 ? moveToX : moveToXDefault)=0A= =0A= if (window.screen.height && height > 0)=0A= moveToY =3D Math.ceil((window.screen.height - height)) - yAdj=0A= moveToY =3D (moveToY > 0 ? moveToY : moveToYDefault)=0A= }=0A= catch (e) {}=0A= =0A= var wLeftTopCornerOptions =3D ',left=3D' + moveToX + ',top=3D' + = moveToY + ',screenX=3D' + moveToX + ',screenY=3D' + moveToY=0A= =0A= allOptions =3D allOptions + wLeftTopCornerOptions=0A= =0A= w =3D window.open ("", windowname, allOptions)=0A= w.focus()=0A= =0A= link.target=3Dwindowname=0A= }=0A= =0A= =0A= //=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D= =3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D= =3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D= =3D=3D=3D=3D=3D=0A= function focuswin(windowname)=0A= {=0A= windowname =3D String(windowname).replace(/-/g, "_")=0A= w =3D = window.open("",windowname,"menubar=3Dyes,scrollbars=3Dyes,toolbar=3Dyes,l= ocation=3Dyes,status=3Dyes,directories=3Dyes,resizable=3Dyes");=0A= w.focus();=0A= =0A= return true;=0A= }=0A= =0A= =0A= //=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D= =3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D= =3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D= =3D=3D=3D=3D=3D=0A= function reverseString (inStr)=0A= {=0A= var outStr =3D ''=0A= =0A= for (i =3D0; i <=3D inStr.length; i++)=0A= {=0A= outStr =3D inStr.charAt(i) + outStr=0A= }=0A= =0A= return outStr=0A= }=0A= =0A= =0A= //=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D= =3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D= =3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D= =3D=3D=3D=3D=3D=0A= function reverseAndReplaceString (inStr, findStr, newStr)=0A= {=0A= return reverseString(inStr).replace(findStr, newStr)=0A= }=0A= =0A= //=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D= =3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D= =3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D= =3D=3D=3D=3D=3D=0A= function initUnObscureEmail (className, innerHTML)=0A= {=0A= =0A= try{=0A= if (window.addEventListener)=0A= window.addEventListener('load', function() {unObscureEmail = (className, innerHTML)}, false)=0A= else if (window.attachEvent)=0A= window.attachEvent('onload', function() {unObscureEmail = (className, innerHTML)})=0A= }catch(e){=0A= }=0A= }=0A= =0A= //=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D= =3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D= =3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D= =3D=3D=3D=3D=3D=0A= function unObscureEmail (className, innerHTML)=0A= {=0A= try {=0A= if (typeof(unObscuredEmails) =3D=3D 'undefined')=0A= unObscuredEmails =3D new Array()=0A= =0A= if (! 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