Role of stereotactic radiosurgery and = fractionated stereotactic radiotherapy for the treatment of recurrent = glioblastoma multiforme; Neurosurgical FOCUS

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December 2009 = Volume 27, Number = 6

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Role of stereotactic radiosurgery and = fractionated stereotactic radiotherapy for the = treatment of=20 recurrent glioblastoma multiforme

Pantaleo Romanelli,=20 M.D.¹, Alfredo Conti, M.D.,=20 Ph.D.², Antonio Pontoriero,=20 M.D.³, Giuseppe=20 Kenneth Ricciardi, M.D.⁴, Francesco Tomasello,=20 M.D.², Costantino De Renzis,=20 M.D.³, Gualtiero Innocenzi,=20 M.D.¹, Vincenzo Esposito,=20 M.D.¹, and Giampaolo Cantore,=20 M.D.¹

¹Department of = Neurosurgery,=20 Istituto di Ricovero e Cura a Carattere Scientifico = Neuromed,=20 Pozzilli; = ²Departments=20 of Neurosurgery and=20 ³Radiation Oncology, University of Messina; = and = ⁴Department of=20 Neuro-radiology, University of Verona, = Italy

Abbreviations used in this = paper:=20 BCNU =3D bischloroethylnitrosourea; EBRT =3D external = beam=20 radiotherapy; fSRT =3D fractionated stereotactic = radiotherapy;=20 GBM =3D glioblastoma multiforme; KPS =3D Karnofsky = Performance=20 Scale; LINAC =3D linear accelerator; RPA =3D recursive = partitioning analysis; RTOG =3D Radiation Therapy = Oncology=20 Group; SRS =3D stereotactic radiosurgery; TMZ =3D=20 temozolomide.

Address correspondence = to:=20 Pantaleo Romanelli, M.D., Functional Neurosurgery, = IRCCS=20 Neuromed, Via Atinense 18, Pozzilli, 86077, IS, Italy. = email:=20 radiosurgery2000@yahoo.com.

DOI: 10.3171/2009.9.FOCUS09187

Figures = and Tables=20

Abstract	IntroductionSupplementing Radiation = D...Stereotactic = Radiosurgery...Criteria for the = Selectio...Future = PerspectivesConclusionsDisclaimerReferences

Glioblastoma multiforme (GBM) = is a=20 devastating malignant brain tumor characterized by = resistance=20 to available therapeutic approaches and relentless = malignant=20 progression that includes widespread intracranial = invasion,=20 destruction of normal brain tissue, progressive = disability,=20 and death. Stereotactic radiosurgery (SRS) and = fractionated=20 stereotactic radiotherapy (fSRT) are increasingly used = in=20 patients with recurrent GBM to complement traditional=20 treatments such as resection, conventional external = beam=20 radiotherapy, and chemotherapy. Both SRS and fSRT are = powerful=20 noninvasive therapeutic modalities well suited to = treat focal=20 neoplastic lesions through the delivery of precise, = highdose=20 radiation. Although no randomized clinical trials have = been=20 performed, a variety of retrospective studies have = been=20 focused on the use of SRS and fSRT for recurrent GBMs. = In=20 addition, state-of-the-art neuroimaging techniques, = such as MR=20 spectroscopic imaging, diffusion tensor tractography, = and=20 nuclear medicine imaging, have enhanced treatment = planning=20 methods leading to potentially improved clinical = outcomes. In=20 this paper the authors reviewed the current = applications and=20 efficacy of SRS and fSRT in the treatment of GBM, = highlighting=20 the value of these therapies for recurrent focal=20 disease.

KEYWORDS:stereotactic = radiosurgery;=20 image guidance; fractionated stereotactic = radiotherapy;=20 robotics; glioblastoma multiforme; recurrent = disease.

Introduction	AbstractIntroduction = <<Supplementing Radiation = D...Stereotactic = Radiosurgery...Criteria for the = Selectio...Future = PerspectivesConclusionsDisclaimerReferences

Glioblastoma = multiforme is the=20 most common and aggressive primary malignant brain = tumor in=20 adults. Despite recent advances in neuroimaging, = surgical=20 techniques, and adjuvant therapies such as = chemotherapy and=20 EBRT, GBM has a dismal prognosis, with local = recurrence=20 remaining the most common form of relapse in more than = 80% of=20 patients.^32,84 Surgical=20 treatment of a focal recurrence can lead to prolonged = growth=20 control,² = but this=20 procedure is only offered to a small = subpopulation.¹ = Systemic=20 chemotherapy provides a modest survival advantage, = with the=20 median survival ranging from 4 to 7 months in patients = with=20 recurrent disease.^7,8,10,16,57=20 Stereotactic radiosurgery, fSRT, and brachytherapy are = logical=20 adjuncts to current state-of-the-art treatments for = recurrent=20 GBM because of their ability to deliver high doses of=20 radiation to a focal target. In comparing these = options,=20 radiosurgery appears to be the most convenient, = offering a=20 fast, noninvasive treatment that can be completed in = one day,=20 is usually well tolerated, and can be repeated.

The main limitation of focal treatments is their = inability=20 to address diffuse disease, which in many cases has = already=20 developed microscopic lesions far beyond the limits of = appreciable radiological boundaries. Nonetheless, = developments=20 in medical imaging have enabled the neurosurgeon to = accurately=20 visualize functional and biomolecular data from both = the=20 normal and diseased brain. New modalities of = information may=20 complement simple anatomical representations of the = brain to=20 facilitate safer and more efficient therapeutic = approaches to=20 brain tumors. In particular, the inclusion of PET and = MR=20 spectroscopic, fMR, and diffusion tensor imaging in = treatment=20 planning can enhance the coverage of diseased brain = areas by=20 showing the diffusion of gliomas along pathways = following the=20 subcortical fiber tracts, the presence of distant = regions of=20 hypermetabolism, and the involvement of critical = areas. This=20 information can help define a planning target volume = that is=20 not simply a geometrical expansion of the gross tumor=20 volume.

On these bases, the ability to deliver = focal=20 high-dose radiation, ablating a selected volume while=20 preserving normal tissue, has a valuable role in the = global=20 treatment of recurrent disease. A number of early=20 retrospective studies on the use of SRS and fSRT for = recurrent=20 GBM have shown promise.^{15,21,23,30,33,34,36,40,43,44,47,53,61,67,81,86} In this=20 paper, we discuss the role of SRS and fSRT in the = multimodal=20 treatment of this disease, with particular emphasis on = the=20 treatment of focal relapse.

Supplementing Radiation Doses = to=20 Recurrent High-Grade Gliomas	AbstractIntroductionSupplementing Radiation D...=20 <<ConclusionsDisclaimerReferences

Treatment modalities delivering highly focused = radiation=20 can be used to boost the dose delivered to a GBM via=20 conventional irradiation techniques while minimizing = radiation=20 exposure to adjacent areas of brain. The goal of local = GBM=20 treatments is to increase the duration of survival = while=20 maintaining an acceptable quality of life for the = patient. The=20 various methods of adding radiation doses are SRS, = fSRT, and=20 brachytherapy (with or without hyperthermia) with the=20 implantation of seeds or a novel brachytherapy device = called=20 the GliaSite Radiation Therapy System (Cytyc Corp.). = Two large=20 Phase III trials have been focused on = brachytherapy;^39,62 standard=20 EBRT alone was compared with EBRT plus low-activity=20 ¹²⁵I seed implants, but no significant = survival=20 advantage was demonstrated by the addition of = brachytherapy.=20 Smaller Phase II studies have yielded various = results.^{29,31,42,54,68} The=20 addition of hyperthermia to brachytherapy has = demonstrated a=20 statistically significant survival advantage in 2 = small=20 patient cohorts.^70,72 Despite=20 these favorable results, no largescale randomized = study has=20 been performed to confirm these findings. The = implantation of=20 permanent ¹²⁵I seeds has also been = described=20 recently. Permanent low-activity seeds seem to be = associated=20 with lower rates of radiation necrosis^29,31,42,54 compared=20 with the rates resulting from the implantation of = temporary=20 high-activity seeds.^5,69,85

A new approach to brachytherapy is the GliaSite = Radiation=20 Therapy System, a balloon catheter system implanted in = the=20 surgical cavity that includes a reservoir to hold an = aqueous=20 solution of organically bound ¹²⁵I (sodium=20 3-[¹²⁵I]-iodo-4-hydroxybenzenesulfonate, or = Iotrex)=20 to deliver low-dose radiation through a subcutaneous=20 port.⁷⁹ The=20 efficacy of GliaSite brachytherapy was assessed in 24 = patients=20 with recurrent GBM.¹¹ The=20 median survival duration following GliaSite treatment = was 9.1=20 months and was comparable to historical data. Patients = with a=20 KPS score of at least 70 survived longer than those = with a=20 score < 70 (9.3 months compared with 3.1 months,=20 respectively; p =3D 0.003). Although this approach has = been=20 shown to be feasible and safe in patients with = recurrent=20 malignant glioma, it is not in widespread use because = of the=20 absence of large-scale, randomized clinical data; the=20 inconvenience to the patient, who must be isolated = during=20 treatment; and the necessity of a second surgery to = remove the=20 delivery system once treatment is completed. = Furthermore, the=20 application of GliaSite is limited to patients with = small,=20 superficial lesions that are amenable to = resection.

While the main limitation of brachytherapy is its=20 invasiveness, SRS and fSRT are virtually noninvasive,=20 especially when frameless technologies are = used.^59,60 Although=20 various terms exist in the literature, the term = =E2=80=9CSRS=E2=80=9D=20 typically refers to single-fraction stereotactic = radiation=20 treatment, whereas the term =E2=80=9CfSRT=E2=80=9D is = used when several=20 stereotactic radiation fractions are delivered.=20 Hypofractionated radiosurgery is an emerging technique = for=20 delivering highly precise and accurate irradiation, = dividing=20 the total dose in up to 5 fractions.³ = Devices=20 suitable for SRS and fSRT treatment include = LINAC-based=20 systems that use x-ray beams generated from a linear=20 accelerator and a stereotactic frame for target = localization.=20 The Gamma Knife (Elekta) utilizes 201 individual=20 ⁶⁰Co gamma ray sources placed within a = helmet-like=20 configuration. A stereotactic frame is required to = immobilize=20 the head and precisely direct the cross-fired beams to = the=20 target. The CyberKnife (Accuray, Inc.) is a robotic,=20 LINAC-based radiosurgery device that obviates the need = to=20 apply an invasive frame to the patient's skull. The = Novalis=20 LINACbased device (BrainLAB) offers frame-based = treatment for=20 SRS and frameless treatment for fSRT.

Initial enthusiasm for SRS as an = adjunct in=20 glioma management was dampened after the publication = of data=20 from a large Phase III study conducted by Souhami and=20 coworkers⁷¹ on=20 behalf of the RTOG. In this study, 203 patients with = newly=20 diagnosed malignant gliomas were randomized to receive = EBRT=20 plus BCNU or SRS plus EBRT plus BCNU. Data in this = study=20 failed to demonstrate a survival advantage in the = patients who=20 received the additional SRS boost as part of the = initial=20 management strategy. The SRS group had a median = survival time=20 of 13.5 months, whereas the control group had a median = survival of 13.6 months. While the authors concluded = that SRS=20 before EBRT and BCNU did not improve survival for = newly=20 diagnosed GBM, they did not address the delivery of = SRS alone=20 as a boost or the use of SRS in the treatment of = recurrent=20 disease.

Stereotactic Radiosurgery and = fSRT for=20 the Treatment of Recurrent GBM	AbstractIntroductionSupplementing Radiation = D...Stereotactic Radiosurgery...=20 <<ConclusionsDisclaimerReferences

Authors of several retrospective studies (Table 1) = have=20 reported that SRS is associated with prolonged = survival in=20 patients with recurrent GBM. These studies have shown = median=20 survival times ranging from 7.5 to 30 months.^{23,30,33,36,40,47} A recent=20 case-control study has indicated that patients with = recurrent=20 GBM treated with SRS require fewer surgical procedures = and=20 experience a slightly longer survival as compared with = untreated patients.⁴⁷ This and=20 other retrospective studies have suggested a = life-prolonging=20 effect of SRS in the management of recurrent = GBM.^33,40,67

TABLE 1: = Summary of=20 published studies on radiosurgery = treatments for=20 recurrent GBMs*

Kondziolka et al.³⁶ have=20 evaluated the survival benefit of SRS in 64 patients = with GBM=20 compared with historical controls. In contrast to = those in the=20 study by Souhami and colleagues,⁷¹ patients=20 received adjuvant SRS 5=E2=80=938 months after the = initial diagnosis=20 (and after other therapies had been completed, = including EBRT=20 and chemotherapy) either before or at the time of = disease=20 progression. The median survival time after the = initial=20 diagnosis was 26 months, the median survival time = after=20 radiosurgery was 21 months, and the 2-year survival = rate was=20 51%. Kondziolka and colleagues³⁶ have=20 also reported a median survival of 30 months after = treatment=20 in patients who underwent SRS at the time of tumor=20 progression.

Linear accelerator=E2=80=93based radiosurgery has = also been used in=20 the treatment of high-grade gliomas.^66,67 Shrieve=20 et al.⁶⁷ have=20 reported data on 86 patients who had undergone LINAC = SRS at=20 the time of tumor recurrence (median radiation dose 13 = Gy,=20 median tumor volume 10.1 cm³). The median = duration=20 of actuarial survival was 10.2 months. The 12- and = 24-month=20 survival rates were 45 and 19%, respectively. These = authors=20 identified 2 prognostic factors: age and tumor volume. = Patients younger than the median age of 46 years had a = median=20 actuarial survival of 15.5 months, compared with 8.2 = months=20 for older patients (p =3D 0.005). Those with tumor = volumes=20 smaller than 10.1 cm³ also survived longer = after=20 SRS than the patients with larger tumors; median = survivals=20 were 15.1 and 8.1 months, respectively (p =3D 0.007). = Both a=20 young age and a small tumor v olume remained positive=20 prognostic factors on multivariate analysis (relative = risk=20 0.829 and 0.707, respectively; p < 0.005). = According to=20 those data the addition of a radiosurgery boost = appears to=20 confer a survival advantage.

A number of retrospective studies have been = published on=20 the treatment of recurrent GBM using fSRT regimens (Table 1).=20 Combs et al.²¹ have=20 published a retrospective study on 59 patients with = recurrent=20 GBM. The median survival following fSRT was 8 months, = with an=20 overall median survival of 21 months from the time of = initial=20 diagnosis. These authors concluded that fSRT was a = safe and=20 well-tolerated strategy warranting further evaluation. = Vordermark et al.⁸¹ have=20 performed a retrospective study of 14 patients with = recurring=20 GBMs that were treated with 4=E2=80=936 fractions of 5 = Gy of=20 radiation. Overall survival in those receiving a total = dose of=20 30 Gy of radiation was 11.1 months, as compared with = 7.4=20 months in those receiving < 30 Gy. The median = survival for=20 all patients was 9.3 months from the time of fSRT. = These=20 authors also found that the combination of fSRT with = other=20 salvage treatments was associated with longer-term = survival,=20 whereas the median survival from the time of treatment = was=20 comparable to that with SRS treatments.

TABLE 2: = Example of=20 cumulative normalized total dose delivered = to the=20 tumor (=CE=B1/=CE=B2 =3D 10) and normal = brain (=CE=B1/=CE=B2 =3D 2)*

The CyberKnife is a frameless radiosurgical device = that can=20 be used to deliver SRS or fSRT in regimens depending = on=20 physician criteria, primarily in consideration of the = tumor=20 volume (Fig. 1). = A=20 multicenter study involving treatment facilities = spread across=20 the US and Europe has confirmed a potential role for=20 CyberKnife radiosurgery in the treatment of malignant = gliomas.=20 The study was aimed at establishing local tumor = control of=20 newly diagnosed versus recurrent GBMs as well as = determining=20 if this treatment modality could improve survival=20 rates.⁸⁰=20 Forty-six patients were treated at multiple = institutions=20 between August 2002 and September 2005. Twenty = patients=20 (43.5%) underwent CyberKnife treatment at the time of = initial=20 diagnosis and/or during the first 3 months of their = initial=20 clinical treatment. Twenty-six patients (56.5%) were = treated=20 at the time of tumor recurrence or progression. The = median=20 survival (Kaplan-Meier analysis) among patients = treated with=20 the CyberKnife as an initial clinical therapy was 11.5 = months,=20 as compared with 24 months among those treated at the = time of=20 tumor recurrence or progression; this difference was=20 statistically significant (p < 0.0004). A Cox = proportional=20 hazards survival regression analysis demonstrated that = survival time had no statistically significant = correlations=20 with CyberKnife treatment parameters (maximum dose = [Dmax],=20 minimum dose [Dmin], and number of fractions) or = target=20 volume. Survival time and RPA class was not quite=20 statistically significant between patients who = received=20 CyberKnife treatment as an initial clinical therapy = and those=20 treated at the time of tumor recurrence or progression = (p =3D=20 0.07). The extent of the surgical intervention = significantly=20 affected survival time (p =3D 0.008), especially if a = biopsy=20 procedure as opposed to total tumor resection was = performed (p=20 =3D 0.004). There were no statistically significant = differences=20 in these parameters between newly diagnosed and = recurrent GBM=20 groups (t-test).

View = larger=20 version (110K)

Fig. 1. = Images=20 demonstrating CyberKnife treatment = planning for a=20 recurrent GBM in the right parietal lobe. = Despite=20 the large volume of this lesion, a highly=20 conformal and homogeneous treatment = delivering=20 high doses in a single stage can be = achieved.=20 Treatment planning snapshot illustrating a = 3D=20 simulation of beam trajectories. The = treatment=20 dosimetry is indicated by the isodose=20 lines.

A few studies have also focused on SRS = and fSRT=20 in combination with chemotherapy for recurrent GBMs = (Table 1).=20 One prospective study of SRS in conjunction with = marimastat=20 for recurrent gliomas showed no survival advantage for = patients with recurrent GBM.⁴¹ Other=20 trials have shown that the multimodality treatment of=20 stereotactic radiosurgery, radiotherapy, and = chemotherapy is=20 feasible and well tolerated, with survival times = similar to=20 those for other treatment modalities.^43,44,61,86

Criteria for the Selection of=20 Candidate Patients	AbstractIntroductionSupplementing Radiation = D...Stereotactic = Radiosurgery...Criteria for the Selectio...=20 <<ConclusionsDisclaimerReferences

One limitation of the retreatment of recurrent = malignant=20 glioma is the high risk of radiation-induced = complications. It=20 has been shown that for gliomas, the higher the dose = the=20 longer the patients survive^6,83=E2=80=94but=20 along with a higher dose comes a higher rate of=20 complications.⁴⁸ Such=20 complications include radiation necrosis, cranial = nerve=20 neuropathies, vascular injuries (including carotid = artery=20 stenosis), and severe edema.^25,37 A study=20 by the RTOG evaluated the toxicity of the = radiosurgical=20 treatment of previously irradiated malignant gliomas,=20 escalating the dose to 24 Gy.⁶³ They=20 demonstrated a good tolerance for small and = medium-sized=20 tumors but unacceptable toxicity for larger = lesions.⁶³ Combs et=20 al.²³ have=20 treated 32 patients with recurrent gliomas using SRS; = a median=20 dose of 15 Gy was applied to a median target volume of = 10 ml.=20 During follow-up, no severe treatment-related side = effects=20 were observed, and the median survival from SRS = treatment was=20 10 months. Note, however, that other groups have = reported=20 higher incidences of treatment-related side effects,=20 especially with larger target volumes. In a study = published by=20 Hall et al.,³⁰ 14% of=20 the patients had radiation-induced necrosis, and = survival=20 calculated from the SRS treatment was 8 months. The = comparably=20 high rate of severe side effects might be attributable = to the=20 relatively larger lesion volumes (median 28 = cm³)=20 treated with SRS. The higher rate of necrosis might = also be=20 due to the applied higher median dose of 20 Gy.

One issue the SRS studies raise is the number of=20 reoperations required because of radiation necrosis. = Several=20 of the SRS studies^23,40 have=20 documented high necrosis-related reoperation rates = ranging=20 from 10 to 31%.^30,33 Hsieh et=20 al.³³ have=20 suggested that their necrosis-related reoperation rate = of 31%=20 may be attributable to large tumor sizes, but the = cause of=20 radiation necrosis in these cases remains unclear.

Other authors have suggested that fSRT treatments = have a=20 radiobiological advantage^27,46 that can=20 reduce radiation-induced necrosis. Consequently,=20 dose-escalation studies and fSRT treatment regimens = for=20 recurrent GBM were examined. Cho et al.¹⁵ have=20 performed a retrospective analysis of recurrent GBM = treatment=20 by comparing SRS with fSRT. These authors found that = patients=20 treated using fSRT had survival times comparable with = those in=20 patients treated using SRS even though the prognostic = factors=20 of the fSRT patients were worse before treatment. = Hudes et=20 al.³⁴ have=20 performed a Phase I dose-escalation study in 19 = patients with=20 persistent or recurrent GBM. No Grade 3 toxicities or = need for=20 reoperation were reported in this study. The median = survival=20 time from the completion of fSRT was 10.5 months, with = a 20%=20 1-year survival rate. These authors concluded that = their=20 encouraging results justified additional = dose-escalation=20 studies. Patel et al.⁵³ have=20 reported findings on 36 patients with recurrent GBM. = At the=20 time of recurrence, 26 patients were treated using SRS = with a=20 median dose of 18 Gy to a median tumor volume of 10.4 = ml. Ten=20 patients were treated with fSRT using a radiation dose = of 36=20 Gy in 6 fractions to a median lesion volume of 51.1 = ml. The=20 median survival time after SRS was 8.5 months, = compared with=20 7.4 months after fSRT (p =3D 0.81). The reoperation = rate was not=20 statistically different between the SRS and fSRT = groups. This=20 finding could suggest that the adequate selection of = radiation=20 doses and fractionation in relation to lesion volume = can lead=20 to a good response and low complication rates.

The volume of tumor and relative volume of = irradiated=20 normal brain are therefore critical factors. = Reirradiation of=20 normal perilesional brain tissue can easily result in=20 exceeding the cumulative normalized total dose of > = 100 Gy=20 that is considered critical for the development of=20 radionecrosis in the brain.⁴⁹=20 Dose/volume calculations can be obtained according to = the=20 linear quadratic model, using an =CE=B1/=CE=B2 =3D 10 = for the tumor and an=20 =CE=B1/=CE=B2 =3D 2 for normal brain (Fig. 2). = In Table 2=20 some dose and fractionation examples are listed. The = volume of=20 normal brain included in the isodoses can be = calculated by=20 obtaining the corresponding cumulative normalized = total dose=20 to provide an estimate of the risk of = radionecrosis.

View = larger=20 version (80K)

Fig. 2. = Image showing=20 the target volume (recurrent glioma), = which has a=20 presumptive =CE=B1/=CE=B2 ratio of 10. It = is surrounded by=20 shells of normal, but previously = irradiated,=20 normal brain tissue that has a presumptive = =CE=B1/=CE=B2=20 ratio of 2. The volume of these shells is = defined=20 by the progressively decaying isodose = lines. The=20 dose/volume ratio of the perilesional = tissue can=20 be used to calculate the cumulative = normalized=20 total dose, according to the linear = quadratic=20 model, to estimate the risk of=20 radionecrosis.

Other reported selection criteria for treatment = include a=20 KPS score of at least 50=E2=80=9360, a life expectancy = > 3 months,=20 a younger age, and a histopathological diagnosis of = GBM.=20 Larson et al.⁴⁰ have=20 analyzed selection factors for a variety of primary = and=20 recurrent WHO Grade II=E2=80=93IV gliomas. They found = that the=20 favorable criteria for SRS included unifocal tumors; = tumors=20 located in hemispheric, supratentorial subcortical = sites; a=20 patient age younger than 70 years; and a KPS score = > 60.=20 Shrieve et al.⁶⁷ have=20 found that increased survival times were associated = with=20 smaller tumors and younger patients. Moreover, SRS = appears to=20 be particularly useful in patients with a KPS score of = at=20 least 90.³³ Age and=20 KPS score are combined in the RTOG RPA classification. = The RPA=20 classification was a significant predictor of survival = on=20 multivariate analysis in a recent report by Pouratian = et=20 al.⁵⁵ In=20 particular, RPA Class 3 patients (age < 50 years = and KPS=20 score > 90) had a median overall survival of 34.5 = months.=20 The benefit of SRS was present but not as great in RPA = Class 4=20 and 5 patients. Table 3 = provides a=20 summary of factors from the above studies that may = affect the=20 outcomes of SRS and fSRT for recurrent GBM.

TABLE 3: = Factors that=20 may affect the outcomes of SRS or fSRT for = recurrent=20 = GBM

Future = Perspectives	AbstractIntroductionSupplementing Radiation = D...Stereotactic = Radiosurgery...Criteria for the = Selectio...Future Perspectives = <<ConclusionsDisclaimerReferences

The combination of new technologies for highly = conformal=20 radiation delivery and advanced neuroimaging methods = may offer=20 the opportunity for improved results in the treatment = of=20 high-grade gliomas. The most likely reason why = radiotherapy is=20 not very effective in long-term disease control lies = in the=20 failure to identify the spreading pattern of gliomas. = With=20 current radiation treatment modalities, the volume to = be=20 irradiated typically incorporates a 20-mm isotropic = margin to=20 account for microscopic tumor spread; however, distant = or=20 progressive tumors occur outside this margin. = Furthermore,=20 both target definition and tumor grading with = conventional MR=20 imaging data to plan radiation therapy have = limitations. The=20 Gd-enhancing lesion, as seen on T1-weighted MR = imaging,=20 reflects regions where there has been a breakdown of = the=20 bloodbrain barrier. The enhancing lesions may not be a = reliable indicator of active tumor because of the = concomitant=20 presence of nonenhancing actively growing tumor = tissue.=20 Similarly, a T2-defined volume either overestimates or = underestimates the microscopic or nonenhancing disease = in a=20 majority of patients.²⁶

Advancements in defining the target = volume=E2=80=94as provided by=20 state-of-the-art neuroimaging such as MR spectroscopic = imaging, diffusion tensor tractography, and nuclear = medicine=20 imaging methods (Fig. = 3)=E2=80=94offer new=20 chances to improve the evaluation of gross tumor = volume and=20 clinical target volume. Advanced neuroimaging = techniques and=20 metabolic imaging may disclose brain areas in which = tumor=20 diffusion is already present, notwithstanding the = absence of=20 contrast enhancement on conventional anatomical = imaging. In=20 particular, MR spectroscopy and PET can provide = information on=20 the altered metabolic activity of tumor cells and = functionally=20 critical brain tissues, and so guiding the dose = painting in=20 the treatment planning for gliomas; functional MR = imaging=20 complements the definition of the target volume by = guiding the=20 orientation of the beams to decrease the dose to = critical=20 areas.^12,52

View = larger=20 version (72K)

Fig. 3. = Upper:=20 Images showing the superimposition of = multivoxel=20 MR spectroscopic images over conventional=20 contrastenhanced MR images with conversion = of the=20 Cho:NAA ratio into a color scale, which = can be=20 incorporated into the SRS/fSRT treatment = planning=20 for recurrent gliomas to add information = on the=20 altered metabolic activity of tumor cells. = In this=20 case, higher tumor infiltration is shown = in the=20 contralateral hemisphere through the = corpus=20 callosum and lateral to the surgical = field.=20 Lower: Contrast-enhanced = T1-weighted MR,=20 T2-weighted MR, MR spectroscopic, CT-PET, = and=20 perfusion MR images demonstrating an SRS = treatment=20 plan for recurrent glioma to define a = biological=20 treatment volume.

According to these initial studies, biological = image-guided=20 radiation therapy, coupled with current anatomical = imaging=20 technologies will optimally deliver radiation with a = high=20 degree of geometrical precision and biological = conformity.=20 Preliminary experience with the definition of = biological=20 target volumes using metabolic imaging has resulted in = substantial changes in target volumes for the planning = of=20 radiation therapy.^13,45

Diffusion tensor imaging, a technique that displays = the=20 distribution and abnormalities of white matter fibers=20 resulting from tumor infiltration, has also been = included in=20 the treatment planning for gliomas. In one study = elongated=20 treatment margins along the paths of increased water = diffusion=20 and altered metabolic activity were included in the = treatment=20 volume, to some extent creating a model of tumor=20 diffusion.³⁵=20 Including a diffusion prediction model generates a = further=20 radiobiological parameter that is the image-based = high-risk=20 volume. Future fSRT and SRS treatment volumes could be = modified according to the biological tumor volume and=20 image-based high-risk volume, and thus create a = biologically=20 better treatment plan that may reduce the incidence of = progression.³⁸

Another opportunity to improve the efficacy of SRS = and fSRT=20 in the management of recurrent GBMs presents itself in = enhancing the biological effect of focal irradiation = through=20 the use of systemic agents working as = radiosensitizers.=20 Several new drugs for the treatment of GBMs are being=20 developed with the intention of achieving increased=20 sensitivity to radiation; some of these agents may = also exert=20 cytotoxic activity on distant cell clones. These new = drugs can=20 be classified as hypoxic sensitizers, Sphase = sensitizers,=20 cytotoxic agents, and targeted agents to be used as=20 sensitizers.¹⁴

Many of these agents have failed to demonstrate = significant=20 activity, but others are still under investigation. = Briefly,=20 hypoxic sensitizers, such as imidazoles, efaproxiral, = and=20 tirapazamine, did not show a significant advantage = when used=20 in combination with EBRT in different Phase II = trials;¹⁴ other=20 agents, such as trans sodium crocetinate, are = undergoing=20 preclinical investigation.^64,65=20 Disappointing results were also obtained with the = S-phase=20 sensitizers, such as bromodeoxyuridine, as well as for = the=20 cytotoxic agents including camptothecins, platinum = agents, and=20 taxanes. Different is the case for TMZ, an alkylating = agent=20 with activity in primary and recurrent gliomas;^{9,51,73=E2=80=9378}=20 preclinical data have shown additive or even = synergistic=20 activity in combination with radiotherapy. Current = data=20 suggest that the most significant benefit with TMZ is = gained=20 from its activity as a radiosensitizer, and additional = data=20 indicate that even low doses have clinically = significant=20 activity with lower rates of toxicity.^{18=E2=80=9320,22} On-going=20 trials are investigating TMZ in combination with other = novel=20 chemotherapy, targeted, and radiosensitizing agents = such as=20 the epidermal growth factor receptor/tyrosine kinase = inhibitor=20 erlotinib and the platelet-derived growth = factor/tyrosine=20 kinase inhibitor imatinib.^56,58

Possible efficacy has been = demonstrated and=20 studies of other biomolecular target agents are = ongoing=E2=80=94for=20 example, mTOR inhibitors (temsirolimus and = RAD001),²⁸=20 farnesyltransferase inhibitors (tipifarnib),¹⁷=20 antiangiogenesis agents (thalidomide and = bevacizumab),^4,82 and the=20 oxidating agent motexafin Gd.⁵⁰ Although=20 markedly improved survival has not been associated = with=20 irradiation and radiosensitizers, this approach = remains very=20 attractive and worthy of further study.

Conclusions	AbstractIntroductionSupplementing Radiation = D...Stereotactic = Radiosurgery...Criteria for the = Selectio...Future = PerspectivesConclusions = <<DisclaimerReferences

Stereotactic radiosurgery and fSRT are = noninvasive well-tolerated treatments that can be = combined=20 with chemotherapy or other adjuvant therapies. In = patients=20 with diagnostically established GBM, recurrent disease = can be=20 treated even if conventional fractionated radiotherapy = (EBRT)=20 has been used previously. To date, the majority of = data=20 published on SRS and fSRT for recurrent GBM have come = from=20 retrospective studies. Interestingly, all of these = studies=20 have suggested a survival benefit after SRS or fSRT = for=20 recurrent GBM, especially in younger patients with a = good=20 performance status^33,66 and=20 smaller tumors.⁴⁴ As=20 nonrandomized retrospective studies, however, these = studies=20 may have a selection bias toward patients whose = treatment=20 outcomes are more favorable.²⁴=20 Prospective randomized trials are needed to discard = this=20 possibility. Nevertheless, the consistent finding of a = survival benefit despite the varied selection criteria = and=20 treatment parameters in these retrospective studies is = encouraging. Stereotactic radiosurgery and fSRT = deserve=20 further investigation for the management of recurrent = GBM with=20 the hope of increasing survival, reducing treatment = side=20 effects, and improving the quality of life for these=20 patients.

Disclaimer	AbstractIntroductionSupplementing Radiation = D...Stereotactic = Radiosurgery...Criteria for the = Selectio...Future = PerspectivesConclusionsDisclaimer <<

The authors report no conflict of = interest=20 concerning the materials or methods used in this study = or the=20 findings specified in this paper.

References	AbstractIntroductionSupplementing Radiation = D...Stereotactic = Radiosurgery...Criteria for the = Selectio...Future = PerspectivesConclusionsDisclaimerReferences = <<

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