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  • 1. J Neurooncol (2008) 89:313–337DOI 10.1007/s11060-008-9617-2 INVITED MANUSCRIPTRadiation therapy of pathologically confirmed newly diagnosedglioblastoma in adultsJohn Buatti Æ Timothy C. Ryken Æ Mark C. Smith Æ Penny Sneed ÆJohn H. Suh Æ Minesh Mehta Æ Jeffrey J. OlsonReceived: 9 January 2008 / Accepted: 19 May 2008Ó Springer Science+Business Media, LLC. 2008Recommendations Hypo-fractionated radiation schemes may be used for patients with a poor prognosis and limited survival withoutLevel 1 compromising response. Hyper-fractionation and accelerated fractionation haveRadiation therapy is recommended for the treatment of not been shown to be superior to conventional fractionationnewly diagnosed malignant glioma in adults. Treatment and are not recommended.schemes should include dosage of up to 60 Gy given in Brachytherapy or stereotactic radiosurgery as a boost to2 Gy daily fractions that includes the enhancing area. external beam radiotherapy have not been shown to be beneficial and are not recommended in the routine man- agement of newly diagnosed malignant glioma. Level 2J. BuattiDepartment of Radiation Oncology, University of Iowa, IowaCity, IA, USA It is recommended that radiation therapy planning include a 1–2 cm margin around the radiographically defined T1T. C. Ryken contrast-enhancing tumor volume or the T2 weightedDepartment of Neurosurgery, University of Iowa College abnormality on MR imaging.of Medicine, Iowa City, IA, USAM. C. SmithDepartment of Radiation Oncology, University of Iowa RationaleHospitals and Clinics, Iowa City, IA, USAP. Sneed Although radiation therapy has been a standard therapy for theDepartment of Radiation Oncology, University of California, treatment of malignant glioma for more than 25 years thereSan Francisco, CA, USA remains controversy as to the optimal way to deliver this ther- apy. Because of several randomized trials in the late 1970s andJ. H. SuhDepartment of Radiation Oncology, Cleveland Clinic early 1980s that showed a benefit with radiation treatment alongFoundation, Cleveland, OH, USA with retrospective series showing that there was a high rate of local recurrence; the stage was set for dose escalation to beM. Mehta studied. Dose escalation in conventional, hyper-fractionated,Department of Radiation Oncology, University of Wisconsin,Madison, WI, USA accelerated and hypo-fractionated radiotherapy was evaluated. Increased local dose was also evaluated including stereotacticJ. J. Olson (&) radiosurgery and brachytherapy. Generally survival has beenDepartment of Neurosurgery, Emory University School used as the endpoint for clinical trials, but increasing interest inof Medicine, 1365B Clifton Rd., NE, Ste. 6200,Atlanta, GA 30322, USA quality of life issues has yielded additional information par-e-mail: jeffrey.olson@emoryhealthcare.org ticularly in the older patients and poor prognostic groups. 123
  • 2. 314 J Neurooncol (2008) 89:313–337 This review focused on the issue of whether radiation The first randomized study was reported by Shapiro intherapy is of benefit in the management of patients diagnosed 1976 and randomized patients to surgery followed bywith malignant glioma. In addition, issues relating to the carmustine (BCNU) and vincristine chemotherapy versusdelivery of this therapy are reviewed, with emphasis on surgery followed by identical chemotherapy along withissues relevant to neurosurgeons involved in the treatment of 45 Gy whole brain radiotherapy and 15 Gy boost dose topatients diagnosed with malignant glioma, including the side ipsilateral to the lesion [2]. The results showed abrachytherapy and radiosurgery. The literature on radiation median survival of 11.1 months in the radiotherapy armsensitizers and proton beam radiotherapy was deferred but is compared to 7.5 months in the chemotherapy only arm.reviewed thoroughly in the excellent systematic review of Despite the apparent survival advantage the difference wasradiation therapy for malignant glioma by Laperriere et al. not statistically significant possibly because only 33for the Neuro-oncology Disease Site Group of the Cancer patients were randomized, three of whom withdrew prior toCare Ontario Program available through the National completing therapy. In addition, the groups were notGuideline Clearinghouse (www.guideline.gov) [1]. evenly matched in terms of Karnofsky Performance Status (KPS) with a mean KPS of 71 in the chemotherapy group compared to 57 in the radiation therapy group, whichSearch criteria further supports the role of radiation therapy. The report also noted that five patients in the radiotherapy group hadA National Library of Medicine literature search was multi-centric or bilateral involvement versus only 2 in theundertaken including the period from 1966 through 2005 chemotherapy alone group.initially using the MESH subject heading astrocytoma gen- In 1978, the first of the BTSG studies addressing theseerating a broad base of studies. Titles and abstracts were issues was reported by Walker et al. [3]. There were 303reviewed with attention to those titles including radiation patients with malignant glioma randomized to one of fourtherapy, radiosurgery, or radioactive implant. Secondary study arms after surgical management. These included asearches crossing astrocytoma with radiation and radiation control of best supportive care alone after surgery, che-therapy were undertaken. Bibliographies of selected papers motherapy alone with BCNU, radiation therapy alone withwere reviewed for additional references of relevance. whole brain radiotherapy to a dose of 50–60 Gy, and a Articles were selected if they addressed issues of radi- combination of BCNU with radiotherapy (identical dosesation therapy of malignant gliomas, dose considerations, and delivery). Of the entire study group 73% were felt tovolume considerations or dose escalation techniques such have been valid for analysis (valid study group), includingas radiosurgery or brachytherapy. Articles were preferen- pathological confirmation and treatment according to thetially reviewed if they contained randomized or prospective protocol. The authors also reported an ‘‘adequately treated’’data. Randomized controlled trials were given preference group that received at least the prescribed dose of radiationas Class I data. Cohort-matched or case–control studies and at least two of the planned courses of BCNU chemo-were given secondary consideration as Class II information therapy. Analysis showed a significant advantage for thoseand institutional reviews with comparisons to historical groups receiving radiation therapy compared to thosecontrols were categorized as Class III data. receiving best supportive care or chemotherapy alone, with a median survival of 4.3 months for the best supportive care arm, 6.3 months in the chemotherapy alone group,Scientific foundation 9.4 months in the radiotherapy alone group and 10.1 month in the group receiving both chemotherapy and radiation.Role of postoperative radiation therapy The results of the later three were all statistically signifi- cant when compared to the surgery alone group. ThisInterest in radiation therapy for primary brain tumors led to provides Class I data supporting a role for radiationa series of randomized, multi-institutional studies, includ- therapy.ing the widely quoted studies by the Brain Tumor Study The follow-up BTSG study reported in 1980 random-Group (BTSG) in the late 1970s and early 1980s. In some ized 467 patients with malignant glioma to semustineinstances these studies provide Class I data addressing the (CCNU) chemotherapy alone, radiotherapy alone, radio-role of radiation therapy in the management of newly therapy plus CCNU or radiotherapy plus BCNU [4]. Thisdiagnosed malignant glioma and demonstrate that it is study again confirmed a significant advantage for theeffective at prolonging the life of patients with malignant groups receiving radiotherapy. The radiotherapy in thisglioma compared to no treatment. In general, these trials trial was better controlled and included specification ofcompared surgery, radiation therapy and chemotherapy 60 Gy in 6–7 weeks. The results in the ‘‘valid study’’ groupalone or in various combinations. that fulfilled protocol criteria indicated a median survival123
  • 3. J Neurooncol (2008) 89:313–337 315of 6 months in the CCNU alone arm, 9 months with were undertaken. However, no clear benefit to escalationradiotherapy alone, 12.8 months with BCNU plus radio- has been demonstrated.therapy and 10.5 months with CCNU plus radiotherapy. A randomized trial of 443 patients reported by theStatistical analysis indicated a significant survival advan- Medical Research Council in the United Kingdom com-tage in radiotherapy containing arms over chemotherapy pared whole brain radiotherapy dosage of 45 Gy in 20alone. This provided additional Class I data supporting the fractions to 60 Gy in 30 fractions for patients with newlyrole for radiotherapy. diagnosed malignant glioma, as described by Bleehen et al. A randomized study in Europe was reported in 1981 by [9]. A two to one randomization scheme placed moreKristiansen, et al. [5]. The study was a three arm ran- patients in the higher dosage scheme. The 1-year survivaldomized, placebo controlled trial following surgical rates were 29% for the 45 Gy arm and 39% for the 60 Gymanagement comparing best supportive care, radiotherapy arm. The 18 month-survival rates were 11% and 18%,alone (with placebo) and radiotherapy combined with respectively and both comparisons were statistically sig-concomitant bleomycin. The radiation in this trial was nificant (P = 0.04). This study provides Class I data45 Gy to the whole brain. Over the course of the study, 118 supporting a dose of 60 Gy compared to 45 Gy.patients were randomized into the three arms with reported In the combined Radiation Therapy Oncology Groupmedian survivals of 5.2 months for the best supportive care (RTOG) and Eastern Cooperative Group (ECOG) trialand 10.8 months for both the combined bleomycin/radio- reported by Nelson et al., 626 patients with newly diag-therapy and radiotherapy alone groups. The authors nosed malignant glioma were randomized to four arms thatindicate this was statistically significant but do not provide included 60 Gy to the whole brain (141 patients), 60 Gy tostatistical detail for review. the whole brain with a 10 Gy boost to the tumor (103 The randomized trial published by Sandberg-Wolheim patients), 60 Gy with carmustine (156 patients) and 60 Gyet al. was conducted in Sweden and included 171 patients with semustine and dacarbazine (138 patients) [10]. Thethat were randomized to receive procarbazine, CCNU and median survival for the 60 and 70 Gy arms was reported asvincristine (PCV) alone or in combination with 50 Gy to 9.3 and 8.2 months. No significant difference in medianthe whole brain and an additional 8 Gy to the ipsilateral survival was found between any of the treatment arms. Thishemisphere for a total of 58 Gy [6]. The analysis included provides Class I data that a dose above 60 Gy is not ben-139 patients in the ‘‘valid study’’ group. In this group the eficial (see Evidentiary Table 2 for further particulars onmedian survival for the chemotherapy only group was the dosage of radiation) [11–13].11.8 months versus 16.5 months with the addition ofradiotherapy (P = 0.01). The trial showed that the addition Volumeof radiotherapy was advantageous and particularly so inthose younger than 50 years of age (median survival Despite the propensity of early whole brain radiotherapy19.3 months versus 30.5 months, P = 0.037). studies, the choice for volume of radiation delivery has Finally, in a systematic review of these six randomized evolved to a more limited field based primarily on naturalstudies addressing the issue of survival advantage created history studies demonstrating a tendency for local recur-by postsurgical external beam radiotherapy, Laperriere rence [14–16] and Class II data suggesting a lack of benefitet al., detected a significant survival benefit [7]. The risk for whole brain radiotherapy compared to more limitedratio of 0.81 (P 0.00001) indicates a reduction in risk of fields. A high percentage of progressive disease is founddying over the course of the studies in patients receiving within 1–2 cm of the initial treatment region. Early studiesradiotherapy as opposed to not receiving it. Thus, even utilized whole brain radiotherapy; however, given thisthough some of the studies contained smaller numbers and information and the advances in neuroimaging, recentdid not achieve individual statistical significance, the years have seen a shift away from utilizing whole braincombined data favors a definite survival advantage with fields to the use of regional fields with margins aroundexternal beam radiotherapy (see Evidentiary Table 1 for enhancing disease, generally on the order of 1–2 cm.further details on the role of postoperative radiation ther- Randomized studies addressing the volume of radio-apy) [8]. therapy delivery have been limited. Shapiro et al. described the BTCG 8001 study in which 571 patients were ran-Dose domized into three chemotherapy regimens [17]. In the early phase of the trial, patients received 60 Gy wholeReview of the literature reveals several randomized trials brain radiotherapy. In the later phases, the protocol wasaddressing the optimal dose of radiotherapy for patients modified and patients received 43 Gy whole brain radio-with malignant glioma. Following the initial success of the therapy and an additional 17 Gy focused on the enhancingBTCG studies, trials using higher total radiotherapy doses volume plus a 2 cm margin. After analysis there was no 123
  • 4. 316 J Neurooncol (2008) 89:313–337Evidentiary Table 1 Postoperative external beam radiationFirst author/ Study description Data class ConclusionReferenceLaperriere et al./[7] Systematic review of randomized trials I Meta-analysis Pooled data detected a significant survival benefit Six randomized studies identified favoring postoperative radiotherapy compared to addressing the role of postoperative no radiotherapy (risk ratio 0.81, 95% CI 0.74– external beam radiotherapy in newly 0.88, P 0.00001). No significant heterogeneity diagnosed malignant glioma following a (v2 = 6.73, P [ 0.10) surgical procedure Two randomized trials showed no difference in survival rates for whole brain radiotherapy versus the enhancing margin plus 2 cm margin. A randomized trial detected a small improvement in survival with 60 Gy in 30 fractions versus 45 Gy in 20 fractions This excellent systematic review supports the role of external beam radiotherapy in patients with newly diagnosed malignant glioma. The data supports inclusion of the enhancing volume plus a margin to a dose of 50 to 60 Gy but is primarily based on studies utilizing whole brain radiotherapy for at least a portion of the treatment regimenSandberg-Wollheim Randomized study of PCV with and I Overall median survival (n = 171): et al./[6] without EBRT (58 Gy total 50 WBRT PCV 10.5 months plus 8 additional to hemisphere) for PCV plus EBRT 15.5 months (P = 0.03) malignant glioma Valid Study Group (n = 139): PCV 11.8 months Overall 171 patients PCV plus EBRT 16.5 months (P = 0.01) Valid study group 139 due to protocol violations Most significant advantage in the Valid Study Group in patients under 50 years of age PCV (n = 71) Median survival PCV plus EBRT (n = 68) PCV 19.3 months PCV plus EBRT 30.5 months (P = 0.037) Median Time to Progression PCV 7 months, PCV plus EBRT 19.8 months (P = 0.08) The authors concluded that EBRT added a significant survival advantage overall which appeared most significant in patients under age 50Kristiansen et al./[5] Randomized study of surgery, surgery II Median survival: plus EBRT (45 Gray whole brain) or Surgery 5.2 months surgery, EBRT and bleomycin Surgery plus EBRT 10.8 months 118 patients with Grade 3 and 4 Surgery plus EBRT and bleomycin 10.8 months (no astrocytoma P-value reported but authors state it was Group 1 Surgery, EBRT and bleomycin statistically significant between surgery alone and (n = 45) the two groups with EBRT) Group 2 Surgery plus EBRT (n = 35) No data on extent of resection and no detail on Group 3 Surgery alone (n = 38) statistical analysis Authors concluded that the addition of radiotherapy doubles survival in patients with malignant glioma over surgery alonedifference in survival between the two different radio- Kita et al. published the results of their randomized trialtherapy regimens. Although this was a randomized study, it in which patients received either 40 Gy whole brainwas not specifically designed to address the issue of radiotherapy in 20 fractions followed with a local boost ofradiotherapy delivery. Therefore there is only Class II data 18 Gy in nine fractions, giving a total dose of 58 Gy, orsupporting the role of limited field therapy. 56 Gy in 28 fractions targeted to the enhancing tumor123
  • 5. J Neurooncol (2008) 89:313–337 317Evidentiary Table 1 continuedFirst author/ Study description Data class ConclusionReferenceWalker et al./[4] Randomized comparison of EBRT (60 I Median survival: Gray whole brain) and nitrosoureas for CCNU 6 months the treatment of malignant glioma EBRT 9 months following surgery EBRT plus BCNU 12.8 months Randomized 467 patients. 358 completed study and formed valid study group EBRT plus CCNU 10.5 months Four arms: Statistical analysis indicated that all groups receiving radiotherapy were significant versus CCNU, EBRT, EBRT plus BCNU, EBRT CCNU alone (P-values from0.001 to 0.016). No plus CCNU significant difference between any of the groups receiving radiotherapy (P-values from 0.11 to 0.67) The authors concluded that the addition of radiotherapy increased median survival in a statistically significant fashion and should be a part of the treatment regimen for malignant gliomaWalker et al./[3] Evaluation of BCNU and/or radiotherapy I Median survival: in the treatment of malignant glioma Surgery alone 4.25 months Randomized 303 patients to best BCNU 6.3 months (P 0.002), supportive care, BCNU, EBRT, EBRT EBRT 9.4 months (P 0.001), plus BCNU EBRT plus BCNU 10.1 months (P 0.006) EBRT 50 to 60 Gray whole brain The authors concluded that the addition of external beam radiotherapy resulted in significant improvement in survival (increasing approximately 150% in this study)Andersen et al. Acta Randomized trial of 108 patients with II Six month survival rates: Radiologica: GBM to surgery or surgery plus EBRT Surgery alone 25% Oncology, (45 Gy whole brain) Surgery plus EBRT 64% (P 0.05) Radiation, 57 patients surgery only Physics, Biology One year survival rates: 51 patients surgery plus EBRT 1978 [8] Surgery alone 0% Surgery plus EBRT 19% (P 0.05) Suggests that EBRT has a significant impact on survival Randomized data but not clear if groups well- matched and lacks sufficient details to consider Class I evidenceShapiro and Young/ Randomized study of BCNU and II Median survival–no statistically significant [2] Vincristine alone (n = 17) or with difference demonstrated EBRT (n = 16) (60 Gy–4500 whole 7.5 months versus 11.1 months (favors the addition brain plus 1500 boost ipsilateral) of radiotherapy) No statistical analysis Incomplete follow-up. Pathology groups are combined Not clear if groups are well matched. Unable to determine extent of resection Survival using combination of radiotherapy and chemotherapy following surgery was significantly better than other studies at that time and the authors encouraged continued investigation of combination radiation and chemotherapy 123
  • 6. 318 J Neurooncol (2008) 89:313–337Evidentiary Table 2 DoseFirst author/Reference Study description Data class ConclusionBleehen and Stenning/[8] Randomized 443 patients to 45 Gy in 20 I Statistically significant difference correlating fractions or 60 Gy in 30 fractions. to an improvement in median survival Patients were randomized in a 2:1 ratio of 2 months in the 60 Gy arm (P = 0.04)Nelson et al. NCI Monogr. 626 patients randomized to 4 study arms: I No statistically significant differences in 1988 [12] 60 Gy to whole brain; survival for any of the 4 arms 60 Gy to whole brain plus a 10 Gy boost; 60 Gy plus carmustine 60 Gy plus semustine and dacarbazineChang et al. Cancer 1983 Randomized controlled trial of RTOG and I No significant improvement in survival [11] ECOG. Four study groups with the 10 Gy boost when compared 60 Gy whole brain radiotherapy, to 60 Gy whole brain alone 60 Gy whole brain radiotherapy plus 10 Gy local boost (total 70 Gy), 60 Gy whole brain radiotherapy plus BCNU 60 Gy whole brain radiotherapy plus CCNU and dacarbazine,Walker MD Int J Radiat Pooled data from randomized BTSG II Re-analysis of BTSG studies with EBRT Oncol Biol Phys 1979 [13] studies 66-01, 69-01 and 72-01 doses from 4500 to 6000 showing best survival using 6000 at 10.5 months survival. The authors suggest that a dose response is demonstrated within this study Dose (Gy) Median survival (months) 60 10.5 55 9.0 50 7.0 45 or less 3.4volume [18]. The authors reported no significant difference treatment. Terminology has developed in attempt to describein survival between the two groups. The 2-year survival these alterations and can be somewhat confusing as thewas 43% for the whole brain group versus 39% for the techniques invariably have some overlap. The comparison islocal field group and 17% versus 27% at 4 years. The study typically made to what may be loosely defined as a con-consisted of a small number of patients (23 and 26 patients ventional dose of approximately 60 Gy given in 30 fractionsrespectively). This is additional Class II data supporting of 2 Gy over 6 weeks. Compared with conventional radio-more limited fields. therapy, hyper-fractionated radiotherapy is generally given Although using an accelerated fractionation scheme, the to a higher total dose over a similar overall treatment timestudy of Phillips et al. randomized 68 older patients using multiple small fractions daily. The theoretical advan-(median age 58–59 years) with newly diagnosed glioblas- tage is the ability to deliver a higher dose without increasedtoma to either conventional fractionated therapy of 60 Gy toxicity, because of the smaller fraction size. The theoreticalin 30 fractions over 6 weeks or to 35 Gy in 10 fractions of advantage of hypo-fractionation is that a shorter overallwhole brain radiotherapy [19]. This study also demon- treatment time should enable better control of the tumor. Instrated no significant difference in survival comparing the most extreme case of hypo-fractionation, single fraction10.3 months for conventional fractionation versus radiosurgery, toxicity is limited by treating a smaller volume.8.7 months for the 35 Gy whole brain radiotherapy group Accelerated radiotherapy refers to a reduction in overall(P = 0.37). See Evidentiary Table 3 for further details on treatment time by delivering multiple daily doses closer tothe volume of tissue radiated. the usual size fraction to a similar overall dose. The basic advantage of accelerated treatments is to reduce overallAltered fractionation schedules treatment time, again assuming that acceptable efficacy and toxicity are obtained.A variety of altered fractionation schemes have been descri- A series of studies are reviewed below using variousbed in attempting to optimize fractionated radiotherapy combinations of altered therapy. These include hyper-123
  • 7. J Neurooncol (2008) 89:313–337 319Evidentiary Table 3 Radiation volumeFirst author/Reference Study description Data class ConclusionKita et al./[18] Randomly assigned 49 patients to receive II Survival rates for whole brain group versus local 40 Gy in 20 fractions to whole brain field were 43% versus 39% at 2 years and followed by a boost of 18 Gy in nine 17% vs. 27% at 4 years (respectively). No fractions; or 56 Gy in 28 fractions via local statistical analysis reported fields Despite the randomized design the study is limited in size and the details of the randomization are not clearShapiro et al./[17] Randomized trial of 571 patients with II No statistically significant differences in survival malignant glioma evaluating three based on altering the radiation volume chemotherapy regimens BTCG Trial 8001 Class II because it was not clear that comparing In the early portion of the study all patients the radiation treatment volume was the initial received 60.2 Gy whole brain radiotherapy. In intent of the study later portions they were randomized to either whole brain radiotherapy or 43 Gy whole brain radiotherapy plus 17.2 Gy to the tumor plus a 2 cm margin.fractionation, hypo-fractionation and accelerated tech- fractionation to a total dose of 47.6 Gy in three times dailyniques. From the review, it would appear that hyper- fractions, hence also accelerated [22]. This study is com-fractionation has perhaps received the most interest. paratively small but also demonstrated no significant differences in survival were identified.Hyper-fractionation Shin et al’s trial published in 1985 compared two frac- tionation schemes: conventional fractionation of 58 Gy inSummaries of the reported randomized trials and two meta- 30 once-daily fractions over 6 weeks versus 61.4 Gy inanalyses are included in the evidentiary tables. three times daily fractions [23]. An additional arm included Prados et al. reported a trial of 231 patients with newly hyper-fractionation plus midonidazole and showed nodiagnosed malignant glioma randomized into two radio- advantage. The authors found an improvement in 1-yeartherapy treatments, accelerated hyper-fractionation with a survival comparing 41% for the hyper-fractionated grouptotal dose of 70.4 Gy at 1.6 Gy twice daily versus con- versus 20% for the conventional fractionation group with aventional fractionation to a total dose of 59.4 Gy at 1.8 Gy P-value of 0.07 which the authors concluded was signifi-daily[20]. Comparison of the two groups demonstrated cant. This paper updated the paper by Fulton et al. [24]similar median survivals (10.5 vs. 10.2 months, respec- which was used in the first of the two meta-analyses notedtively, P = 0.75). below. The Phase I/II dose escalation study described by Nelson An earlier trial by Shin et al. compared conventionallyet al. randomized 435 patients using local fields and 1.2 Gy fractionated whole brain radiotherapy of 34 Gy in 17in twice daily fractions to a total doses of 64.8 Gy, 72.0 Gy, fractions plus a 16 Gy local boost with hyper-fractionated76.8 Gy and 81.6 Gy with median survivals of 11.4, 12.8, (superfractionated) treatments of 40 Gy whole brain in 4512.0, 11.7 months, respectively [10]. The authors were fractions plus 10 Gy local boost [25]. The authors found nounable to demonstrate a statistically significant survival significant difference between the treatment arms andadvantage between any of these groups, but noted a trend noted some imbalances between the two groups.towards increased survival with 72 Gy given in twice-daily Payne et al. randomized 157 patients into two groupsfractions. This dose is approximately biologically equivalent comparing hyper-fractionated radiotherapy to 36–40 Gy into the most standard conventional dose of 60 Gy. four times daily fractions with conventional radiotherapy Deutsch et al. randomized 603 patients into a trial that of 50 Gy in 25 fractions with both groups also receivingincluded randomization to groups receiving conventional CCNU and hydrea [26]. No significant difference in med-fractionation with either BCNU, steptozotocin or misoni- ian survival was noted.dazole or hyper-fractionated radiotherapy plus BCNU [21]. Two meta-analyses of radiation therapy in newly diag-No significant difference in survival was identified. nosed malignant glioma were identified and reviewed. The trial by Ludgate et al. randomized 76 patients to Stuschke and Thames analyzed the pooled data from theeither receive whole brain radiotherapy (40 Gy) plus local trials of Deutsch et al., Fulton et al. and Shin et al. [21] andboost therapy (10 Gy) with daily treatments or hyper- reported a significant survival benefit for patients treated 123
  • 8. 320 J Neurooncol (2008) 89:313–337with hyper-fractionated therapy with an odds ratio of 0.67 Phillips et al. randomized 68 older patients (84% over(95% confidence interval 0.48–0.93, P = 0.02). This report 40 years of age, median age 58–59 years) with newlydid not include the study by Ludgate et al. or, the updated diagnosed glioblastoma to either conventional fractionatedreport on the Fulton trial published as Shin et al. in 1985 therapy of 60 Gy in 30 fractions over 6 weeks or to 35 Gyand it excluded the report by Payne et al. in 10 fractions of whole brain radiotherapy [19]. The study A subsequent meta-analysis by Laperiere et al. pooled was closed prematurely due to poor accrual and was unabledata from the studies by Payne 1982, Shin 1983 Shin 1985 to demonstrate a significant difference, although the med-and Deutsch 1989 [7]. The data from Fulton et al. included ian survival for the conventional group was longer,in the Stuschke and Thames review was included in the comparing 10.3 months for conventional fractionationupdated report by Shin et al. With the inclusion of these versus 8.7 months for the 35 Gy group (P = 0.37).additional larger studies, the authors concluded that no Hulshof et al. described a prospective non-randomizedsignificant survival benefit for hyper-fractionated radio- study examining aggressive hypo-fractionation in a grouptherapy could be identified when compared with of 155 patients with glioblastoma [32]. The schemesconventionally fractionated radiotherapy (RR, 0.89; 95% included 33 fractions of 2 Gy, 8 fractions of 5 Gy andCI, 0.73–1.09; P = 0.27). The analysis indicated no sta- four fractions of 7 Gy. The authors found that the periodtistically significant heterogeneity (v2 = 6.27, P = 0.10). of neurological stabilization was similar between theThe trial by Ludgate et al. was not included because the groups receiving four fractions of 7 Gy versus the con-survival curves were not available for the total study group ventional 33 fractions of 2 Gy and concluded that an(see Evidentiary Table 4 for further details on hyper-frac- aggressive hypo-fractionation scheme in patients withtionation) [27]. poor prognostic indicators was well tolerated and had similar survival results compared with conventionalHypo-fractionation fractionation. Kleinberg et al. retrospectively reviewed 219 patientsThere have been a series of single-arm prospective non- with malignant glioma treated with 51 Gy given as 30 Gyrandomized trials using hypo-fractionation in a variety of in 10 fractions to either large local fields or whole brain,regimens, generally in patients felt to have poor prognostic followed 2 weeks later with 21 Gy in seven fractions tofactors (older age and poorer performance scores). These local fields and stratified the outcomes by RTOG recursiveregimens have generally been attempted to demonstrate partitioning analysis groups [28]. The authors concludedequivalent palliative results to conventional fractionation that for RTOG groups 4–6 the hypo-fractionated regimenbut shorten the overall treatment time, which could have an gave similar survival results when compared to previousimpact on the quality of life in individuals with a short life RTOG trials for malignant glioma treated with conven-expectancy. Several of the papers conclude that caution tional fractionation.should be used in utilizing these regimens in patients with a Ford et al. performed a matched-pair analysis compar-better prognosis because long term cognitive follow-up was ing 27 poor prognosis patients treated with 36 Gy in 12not available [28] and elderly patients who have main- fractions to 27 matched patients treated with 60 Gy in 30tained a KPS greater than 50 may benefit from the standard fractions [33]. Comparison of the groups indicated noconventional fractionated therapies [29]. difference in outcome (Hazard ratio of 1.0, 95% CI 0.57– Sultanem et al. reported a prospective non-randomized 1.74) and the authors concluded that for poor prognosisstudy of 25 patients with glioblastoma treated with a hypo- patients the shorter hypo-fractionated regimen was at leastfractionated regimen of 60 Gy in 20 daily fractions of 3 Gy no worse than conventional fractionation.given over 4 weeks [30]. The median survival was Hoegler et al. published a prospective non-randomized9.5 months. The authors concluded that although no sur- study of 25 patients with a median age of 73 treated withvival advantage seemed to result, the 2 week shorter 37.5 Gy in 15 fractions [34]. Median survival wastreatment time appeared safe and feasible and could be 8.0 months overall and 10.4 months in the group withadvantageous in selected situations. KPS [ 70. The authors concluded for this group that sur- Roa et al. randomized 100 older patients with newly vival was similar to that achieved with conventionaldiagnosed glioblastoma to either conventional fractionation radiotherapy regimens and that a Phase III trial wasof 60 Gy in 30 fractions over 6 weeks or hypo-fraction- warranted.ation of 40 Gy in 15 fractions over 3 weeks [31]. The Slotman et al. treated a group of 30 patients with GBMmedian survivals were 5.1 versus 5.6 months, respectively, in a non-randomized prospective trial with 42 Gy in 14and were not significantly different (P = 0.57). The fractions using local fields [35]. The regimen had accept-authors concluded that in the population over age 60, this able toxicity and was well tolerated. Factors indicative ofhypo-fractionated regimen could be considered. improved survival included age under 50, KPS of 80% to123
  • 9. J Neurooncol (2008) 89:313–337 321Evidentiary Table 4 Hyper-fractionationFirst author/ Study description Data class ConclusionReferenceLaperriere et al./[7] Systematic review of previous randomized I Meta-analysis Pooled analysis included four randomized studies involving hyper-fractionated studies. Two were identified but excluded as radiotherapy for malignant glioma data reporting not consistent Studies included: No significant survival benefit for hyper- Payne 1982 fractionated radiotherapy was identified when compared with conventional radiotherapy Shin 1983 (RR, 0.89; 95% CI, 0.73–1.09; P = 0.27) Shin 1985 No statistically significant heterogeneity Deutsch 1989 (v2 = 6.27, P = 0.10). Not including Scott 1998 (Abstract Only–1 year survival and number per group not reported), Ludgate1988 (no overall survival reported)Prados et al./[20] Randomized controlled trial of 231 patients I No difference in groups with or without DMFO with newly diagnosed GBM in four Accelerated Hyper-fractionated (2 arms): groups comparing accelerated Overall Survival 10.5 months, Standard hyperfractionated radiotherapy (70.4 Gy Radiation Therapy (2 arms): Overall Survival using two fractions per day) versus 10.25 months (P = 0.75) standard fractionated irradiation The authors concluded that there was no survival (59.4 Gy using daily fractions) with or benefit observed with accelerated hyper- without DFMO as a radiosensitizer fractionated therapy Groups balanced with respect to age, KPS, extent of resectionStuschke M et al., Meta-analysis including three previously II Meta-analysis The authors reported a trend in favor of hyper- Int J Radiat Oncol reported randomized trials including fractionation with O.R. of 0.67 (95% CI 0.48– Biol Phys 1997 hyper-fractionation in newly diagnosed 0.93, P = 0.02). [27] malignant glioma Small number of studies limits interpretation Studies included: Deutsch 1989 Fulton 1984 Shin 1983Nelson et al./[10] Randomized controlled trial of 435 II Complicated study to interpret due to the change analyzed patients with newly diagnosed in the radiation doses used over the sequence malignant glioma initially into three arms Median survival: receiving 1.2 Gy fractions twice daily; 64.8 Gy 11.4 months 64.8 Gy 72.0 Gy 12.8 months 72.0 Gy 76.8 Gy 12.0 months 76.8 Gy, and subsequently into two arms: 81.6 Gy 11.7 months 72.0 Gy The authors report no significant differences 81.6 Gy All patients also received BCNU between any of the groups but note the trend Local field radiotherapy used and defined as towards increased survival at the 72.0 Gy dose edema on imaging plus 2.5 cm margin given in twice daily fractions and note similar survival for this group to the survival in previous studies of 60 Gy in daily fractions This trial led to the subsequent RTOG 9006 trial comparing hyper-fractionated radiotherapy to 72.0 Gy in 1.2 Gy fractions twice daily to 60 Gy daily fractions of 2 Gy as reported in abstract form by Scott et al. The results of the subsequent trial involving 712 adults with newly diagnosed malignant glioma did not indicate an advantage to hyper-fractionation over daily fractionation (10.2 months vs. 11.2 months, P = 0.44) 123
  • 10. 322 J Neurooncol (2008) 89:313–337Evidentiary Table 4 continuedFirst author/ Study description Data class ConclusionReferenceDeutsch et al./[21] Randomized controlled trial of 603 patients I Median survivals: with newly diagnosed malignant glioma Standard radiotherapy plus BCNU 9.9 months in four groups: Standard radiotherapy plus streptozotocin Standard radiotherapy plus BCNU 9.9 months Standard radiotherapy (60 Gy in 30–35 Hyper-fractionated radiotherapy plus BCNU fractions) plus streptozotocin 10.4 months Hyper-fractionated radiotherapy (66 Gy in Standard radiotherapy plus misonidazole and 60 fractions–twice daily) plus BCNU BCNU 9.2 months Standard radiotherapy plus misonidazole No statistically significant difference between and BCNU any of the groups and no advantage to hyper- fractionationLudgate et al./[22] Randomized controlled trial of 76 patients I Median survival: with newly diagnosed GBM comparing Daily fraction group 8 months whole brain radiotherapy plus 10 Gy Hyper-fractionated group 11.5 months (P-value local boost delivered daily treatments to reported as not significant) 40 Gy versus three fractions per day to a dose of 47.6 Gy No significant difference in survival was identified. An increase in early radiation reaction and a decrease in late radiation reaction was identified in the hyper-fractionated group. The age of the daily fractionated group was older than the hyper-fractionated group This trial was not included in the Laperiere et al. meta-analysis as the survival curves were reported for three different age groups but not for the total group. It was not included in the meta-analysis by Stuschke et al. for unknown reasonsShin et al./[23] Randomized controlled trial in newly I One year survival rate: diagnosed malignant astrocytoma Coventional fractionation 20% comparing two fractionation schemes Multiple daily fractionation 41% with misonidazole (124 patients): Multiple daily plus midonidazole 45% Conventional fractionation (58 Gy in 30 fractions over 6 weeks) 38 patients versus No significant difference between fractionation Multiple daily fractions (61.4 Gy three schemes favoring multiple daily fractions daily fractions over 4.5 weeks) 43 patients (P = 0.07). No effect of midonidazole versus Multiple daily fractions plus midonidazole 43 patientsShin et al./[25] Randomized controlled trial for newly I One year survival: diagnosed malignant astrocytoma Conventional fractionated therapy 10% comparing: Superfractionated therapy 32% Superfractionated radiotherapy (40 Gy in Two year survival: 45 fractions whole brain with 10 local boost) 34 patients versus conventional Conventional fractionated therapy 21% fractionated radiotherapy (34 Gy in 17 Superfractionated therapy 54% fractions whole brain with 16 Gy local Median survival: boost) 35 patients Conventional fractionated therapy 9 months Superfractionated therapy 13 months The authors note a trend in favor of superfractionation but note that it was not statistically significant and may have been explained by differences between the two groups (primarily age was younger in the superfractionated group)123
  • 11. J Neurooncol (2008) 89:313–337 323Evidentiary Table 4 continuedFirst author/ Study description Data class ConclusionReferencePayne et al./[26] Randomized controlled trial comparing 157 I Median survival: patients with newly diagnosed malignant Hyper-fractionated 10.6 months astrocytoma treated with Standard radiotherapy 10.2 months (P = NS) Hyper-fractionated (36–40 Gy given four No significant survival or toxicity differences fractions per day) versus Standard were seen between the two groups radiotherapy (50 Gy in 25 fractions) Both groups received CCNU and hydreaScott et al. Randomized comparison of hyper- Not Graded Presented as an abstract only. It is included here Proceedings of the fractionated rad iotherapy to 72.0 Gy for reference because it is a large trial that is Annual Meeting versus standard radiotherapy referred to in the literature with some of ASCO 1998 RTOG 9006 frequency 712 patients with malignant glioma Authors reported no significant difference in median survival between the two groups Patients also received BCNU Limited data available precluded this large negative study from being included in subsequent meta-analysis100% and 75% or greater resection. If none of those factors Evidentiary Table 5 for further particulars on hypo-were present the median survival dropped to 6.25 months. fractionation. Bauman et al. treated 29 patients with GBM with poorprognostic factors (age greater than 64 and KPS less than Accelerated radiotherapy50) with 30 Gy whole brain radiotherapy in 10 fractionsover 2 weeks [29]. They compared their median survival of Brada et al. described a single arm non-randomized study6 months with historical controls of 35 similar patients described the treatment of 211 patients with malignanttreated with 50 Gy (median survival of 10.1 months) and glioma treated with 55 Gy in 34 twice daily fractions [38].28 patients receiving supportive care only (median survival The median survival was 10 months. In comparing to aof 1 month). The authors concluded that the hypo-frac- historical control group treated with 60 Gy in 30 fractionstionated course could be used in elderly patients with poor the authors concluded their results were nearly identical.prognosis and that conventional therapy should be con- They added the opinion that given the lack of clear survivalsidered in the elderly patient with a higher KPS. advantage, the logistics of administering multiple fractions Thomas et al. used a scheme of 30 Gy in six fractions per day appeared to be an unnecessary complication.using local fields over 2 weeks in 38 patients with malig- Werner-Wasik et al. published their randomized con-nant glioma and poor prognostic indicators and found a trolled trial evaluating dose escalation, hyper-fractionationmedian survival of 6 months [36]. They felt the regimen and accelerated dosing in 747 evaluable patients (RTOGwas well tolerated and provided effective palliation but 83-02) [39]. The accelerated group received 1.6 Gy twiceindicated definitive conclusions would require randomized daily to doses up to 54 Gy. Although they found lowdata. toxicity with the accelerated regimen, the median survival Glinski et al. published a randomized controlled trial of of 10. 2 months for glioblastoma and 40.3 months for108 patients including 44 with glioblastoma and 64 with anaplastic astrocytoma was not significantly different thananaplastic astrocytoma with two arms: conventional frac- the hyper-fractionated regimen or from historical conven-tionation (50 Gy whole brain plus 10 Gy in five fractions to tionally fractionated controls (10.2 vs. 10.8 months,the tumor) or hypo-fractionation (two courses of 20 Gy in P = 0.08 for glioblastoma and 42.3 versus 40.3 months,five fractions separated by a month and followed a month P = 0.67 for anaplastic astrocytoma).later by 10 Gy in 5 as a boost to the tumor) [37]. The Horiot et al. reported on the results of an EORTC ran-groups appeared to be well balanced. Reporting on the 2- domized controlled trial of 340 malignant glioma patientsyear survival there was no survival advantage for the [40]. The study involved three arms: 60 Gy in 30 fractionsanaplastic astrocytoma groups (22% vs. 18%, P [ 0.05), over 6 weeks (conventional fractionation), 60 Gy total butHowever, they found a survival advantage in the subgroup given in 2 Gy fractions three times daily for 1 weekof 44 glioblastoma patients treated with hypo-fractionated (30 Gy) and then repeated after 2 week interval (acceler-split regimen of 23% versus 10% (P 0.05). See ated fractionation). The third group consisted of the 123
  • 12. 324 J Neurooncol (2008) 89:313–337Evidentiary Table 5 Hypo-fractionationFirst author/ Study description Data class ConclusionReferenceSultanem et al./[30] Prospective trial of 25 patients with GBM III Median survival 9.5 months (range: 2.8–22.9 months) treated with a hypo-fractionated One-year survival rate 40% radiotherapy. 60 Gy in 20 daily Median progression-free survival was 5.2 months fractions of 3 Gy to the tumor volume, (range: 1.9–12.8 months) and 40 Gy in 20 fractions of 2 Gy over The 2-week reduction in the treatment time may be a 4 weeks valuable benefit for this group of patients. However, despite this accelerated regimen, no survival advantage has been observedRoa et al./[31] Randomized controlled trial of 100 I Median survival: patients with newly diagnosed GBM 60 Gy group 5.1 month over age 60. 40 Gy group 5.6 month P = 0.57 Two groups: 6 month survival: 60 Gy in 30 fractions over 6 weeks versus 60 Gy group 44.7% 40 Gy in 15 fractions over 3 weeks 40 Gy group 41.7% No significant difference could be demonstrated. The abbreviated regimen may be reasonable to consider in patients over the age of 60Phillips et al./[19] Randomized controlled trial in newly I Median survival: diagnosed GBM (closed early for slow 60 Gy group 10.3 month accrual) 35 Gy group 8.7 month P = 0.37 84% of all patients were over 40 years of Risk of dying over course of the study appeared age. increased in the whole brain radiotherapy with RR of Two groups: 1.47 (95% CI 0.89–2.42) but was not significant 60 Gy in 30 fractions over 6 weeks–Local field (n = 36) versus 35 Gy in 10 fractions–Whole Brain Radiotherapy (n = 32)Hulshof et al./[32] Prospective non-randomized comparison III Median survival: of conventional and hypo-fractionated 33 9 2 Gy 7 months radiotherapy in GBM 8 9 5 Gy 5.6 months 155 patients Three different radiation 4 9 7 Gy 6.6 months schemes were used; In general, patients in the hypo-fractionation group had 33 9 2 Gy far worse prognostic factors compared with patients 8 9 5 Gy treated with the conventional scheme 4 9 7 Gy The period of neurological improvement or stabilisation was similar between the 4 9 7 Gy and 33 9 2 Gy group An extreme hypo-fractionation scheme of 4 9 7 Gy conformal irradiation in poor prognostic glioblastoma patients is well tolerated, convenient for the patient and provides equal palliation without negative effects on survival compared with conventional fractionationaccelerated fractionated regimen plus misonidazole. of 60 Gy [41]. They found a median survival ofAlthough the detail provided in this paper is minimal, the 10.5 months. Comparison to similar group of 26 patientsauthors reported no significant difference between any of treated with conventional fractionation found no significantthe groups (P-value not reported). They did not describe an difference (P-value not reported). The authors concludedincrease in toxicity with the accelerated regimen. that there were no increased problems with the accelerated Keim et al. described a non-randomized comparison of regimen but it did not improve survival.38 patients with GBM treated with an accelerated radio- Simpson and Platts published a randomized trial of 134therapy regimen of 1.6 Gy three times daily to a total dose patients with glioblastoma initially with three treatment123
  • 13. J Neurooncol (2008) 89:313–337 325Evidentiary Table 5 continuedFirst author/ Study description Data class ConclusionReferenceKleinberg et al./[28] Retrospective review and classification of III The six RTOG prognostic groupings were significantly 219 patients with malignant glioma predictive of outcome for patients treated with this treated with 51 Gy delivered as 30 Gy shortened regimen (log rank P 0.001) in 10 fractions to large field or whole Median Two-Year brain, followed 2 weeks later with survival Survival 21 Gy in seven fractions (months) (%) Outcomes stratified by RTOG RPA RTOG Class 1 68 64 classes RTOG Class 2 57 67 RTOG Class 3 22 45 RTOG Class 4 13 8 RTOG Class 5 8 3 RTOG Class 6 5 3 The median and 2-year survival results for each prognostic classes were similar to the results achieved by aggressive treatment on RTOG malignant glioma trials for selected patients The authors concluded that this decreased regimen could be considered an appropriate treatment option for most malignant glioma patients (RTOG groups 4–6), as it resulted in similar survival as standard regimens with reduced treatment time However, they did not recommend this regimen for RTOG classes 1–3 because long-term neuro- cognitive effects are unknown using this hypo- fractionation schemeFord et al./[33] Matched case–control 32 poor prognosis II 27 pairs were used patients with GBM treated with 36 Gy Median survival for the 36 Gy group was 4 months in 12 fractions Compared with matched Comparison with control group resulted in a Hazard patients receiving 60 Gy in 30 fractions ratio of 1.0 (95% CI was 0.57–1.74) For poor prognosis patients the shorter regimen was no worse than the standardHoegler et al./[34] Prospective non-randomized study of 25 III Median survival (overall group) 8.0 months patients with GBM treated with Median survival (if KPS [ 70) 10.4 months 37.5 Gy in 15 fractions. Median age The authors conclude that for this elderly group the 73 years survival was similar to longer radiotherapy regimens and that a Phase III study was warrantedSlotman et al./[35] Prospective non-randomized study of 30 III Median survival was 9 months for the overall group patients with GBM treated with 42 Gy Three prognostic factors were identified in 14 fractions to the tumor plus 3 cm Median survival: Age under 50, KPS 80 to 100, 75% or greater resection–12.5 months One or two of the above factors–9.5 months None of the above factors–6.25 monthsBauman et al./[29] Prospective single arm trial. 29 patients III Median survival 6 months with GBM poor prognosis (age greater Compared with historical cohorts, 35 similar patients than 64 years or KPS less than 50) treated with greater than 50 Gy (Median survival treated with 30 Gy whole brain in 10 10.1 months) and 28 patients treated with supportive fractions over 2 weeks care only (1 month) The authors conclude that although this lower dose regimen may be useful in poor prognosis older patients, elderly patients with KPS greater than 50 my be considered for higher dose radiotherapy regimens given the historical better outcome 123
  • 14. 326 J Neurooncol (2008) 89:313–337Evidentiary Table 5 continuedFirst author/ Study description Data class ConclusionReferenceThomas et al./[36] Prospective non-randomized study of 38 III Median survival 6 months patients with malignant glioma and One year survival rate 23% poor prognosis treated with 30 Gy in The authors conclude that this hypo-fractionated six fractions over 2 weeks to the regimen was well tolerated, convenient and provided enhancement plus 2 cm effective palliation. They indicated that comparison with conventional radiotherapy or supportive care only would require randomized studiesGlinski/[37] Randomized controlled trial of 108 II An analysis of all 108 randomized patients patients with malignant glioma demonstrated no significant difference in survival (44 GBM, 64 AA). Randomized to two between the treatment arms arms: Conventional fractionation Non-significant difference in the 64 patients with AA (50 Gy Whole brain plus 10 Gy in 5 (22% vs. 18%, P [ 0.05) fraction local boost to the tumor) and Significant survival benefit favoring hypo-fractionated Hypo-fractionated (three courses radiation compared with conventional radiation in separated by one month interval 20 Gy the subgroup of 44 patients with glioblastoma (23% in 5 times two plus 10 Gy in 5 fraction vs. 10% at 2 years; P 0.05) boost) Long-term neuropsychological data is lacking in these groups. The mixed groups limits the numbers and limits interpretationarms [42]. These included whole brain radiotherapy to median survival in the implant group of 18 months versus30 Gy given either as three times daily over 1 week, three 11 months in the control group (P 0.0007) [43]. Similartimes daily over 3 weeks or daily for 3 weeks. As the study encouraging results in non-randomized fashion wereprogressed (presumably based on the safety evaluation and observed by Sneed et al. in two separate reports (medianlack of efficacy) the doses were adjusted upwards to survivals of 19 months) and Chang et al. (median survivalinclude 40 Gy. The authors found no difference in survival 19.5 months with brachytherapy vs. 12.5 months without)between any of the groups in this study (see Evidentiary [44–46]. Effect of dose rate delivered by different isotopesTable 6 for further points on accelerated radiotherapy). was studied by Koot et al. and did not appear to alter the survival [47]. A number of investigators have applied the RTOGBrachytherapy recursive partitioning analysis to brachytherapy series. Videtic et al. evaluated the effect of tumor volume onBrachytherapy is a technique that utilizes the placement of survival, finding that the observed inverse relationshipradioactive seeds in and around tumors to increase, or between tumor volume implanted and survival disappearedboost, the delivery of local radiation. Both temporary and within each RPA class suggesting that even patients withpermanent sources have been described and a variety of larger volumes may benefit from brachytherapy [48].radioactive sources have been utilized, with the majority of Chang et al. evaluated a series of 28 patients stratified bymore recent studies in malignant glioma describing the use RPA class finding an overall trend in favor of brachy-of I-(125). Theoretically this could offer an advantage in therapy but due to the small numbers in each class onlymalignant glioma when the tumors are unifocal at presen- found significance in RPA class 5 [46]. Lamborn et al.tation and because the majority of tumors progress or recur evaluated 832 patients involved in eight different clinicalwithin 2 cm of their original location. Two randomized trials finding that in addition to extent of resection, che-studies, one matched control study and a series of retro- motherapy, age and KPS brachytherapy also had aspective studies of interest are abstracted in the Evidentiary significant effect on survival [49].Table 7. Despite these thoughtful and promising results, there Significant effort has gone into attempting to identify have been two randomized trials of brachytherapy thatpatients with malignant glioma who would benefit from failed to demonstrate a survival advantage for brachyther-this technique. Generally patients selected for brachyther- apy when added to the treatment regimen for newlyapy have good KPS and smaller, more focal tumors. Wen diagnosed malignant glioma. Laperriere et al’s study pub-et al. described a series of matched control patients with a lished in 1998 randomly assigned 140 patients to external123
  • 15. J Neurooncol (2008) 89:313–337 327Evidentiary Table 6 Accelerated radiotherapyFirst author/ Study description Data class ConclusionReferenceBrada et al./[38] Single arm study of 211 patients with III Median survival 10 months, malignant glioma treated with 55 Gy in The authors state that their results are similar to a 34 fractions (twice daily). matched cohort of patients who had received Compared to historical control of similar 60 Gy in 30 fractions over 6 weeks in a previous group treated with 60 Gy in 30 fractions MRC study and felt that a matched comparison over 6 weeks would yield similar results Overall conclusion was that accelerated treatments complicated the logistics for delivery of radiotherapy and added nothing to survivalWerner-Wasik et al./ Randomized controlled dose escalation I Overall median survival for GBM: [39] study randomized to hyper-fractionated Hyper-fractionated 10.8 months (1.2 Gy twice daily to 64.8, 72, 76.8, Accelerated hyper-fractionated 10.2 months 81.8 Gy) or accelerated radiotherapy P = 0.08 (1.6 Gy twice daily to doses of 48 or 54.4 Gy) Overall median survival for AA RTOG 83-02 Hyper-fractionated 42.3 months 786 patients (747 eligible and evaluable) Accelerated hyper-fractionated 40.3 months P = 0.67 81% GBM and 19% AA) Overall analysis indicated no significant survival All patients recieved BCNU difference among any of the dose schemes (P = 0.598). There was low toxicity with accelerated fractionationHoriot et al./[40] Randomized controlled trial (EORTC II Minimal details reported but the authors concluded Protocol 22803. that there was no difference in survival between 340 patients with malignant glioma into the three treatment groups (P-value not three arms. reported). No increased toxicity with accelerated radiation 60 Gy in 30 fractions over 3 weeks 30 Gy in 15 fractions in three daily fractions, interval of 2 weeks then repeat (one group with and one group without misonidazole)Keim et al./[41] Non-randomized comparison of 38 patients III Median survival 10. 5 months. No difference with GBM treated with accelerated between these two treatment groups. P-value radiotherapy (1.6 Gy three times daily to not reported total dose of 60 Gy) compared to 26 The authors concluded that the tolerance of the patients treated with 60 Gy in 30 accelerated schedule was as good as the fractions over 6 weeks conventional but that survival was not improvedSimpson and Platts/ Randomized trial of 134 patients with GBM II No significant difference noted between any of the [42] with three treatment groups groups. All P-values greater than 0.05 Total whole brain dose of 30 Gy (in initial Although reported as a randomized study, the group three times daily for 1 week, three detail included makes evaluation difficult times daily for 3 weeks or daily for 3 weeks) Doses were escalated to 40 Gy in later portions of the study)radiotherapy of 50 Gy in 25 fractions over 5 weeks (69 concluded that stereotactic radiation implants did notpatients) versus the same external radiotherapy plus tem- demonstrate a statistically significant improvement in sur-porary stereotactic iodine-125 implants with a minimum vival in the initial management of patients with malignantperipheral tumor dose of 60 Gy (71 patients) [50]. Median glioma.survival for the brachytherapy arm was 13.8 months versus Although the initial report of the Brain Tumor Coop-13.2 months for the non-brachytherapy arm (P = 0.49). erative Group (BTCG Trial 87-01) randomized trial ofImproved survival was associated with either chemother- radiotherapy plus BCNU with and without interstitialapy or reoperation at progression (P = 0.004) or KPS radiation for a total dose of 60 Gy at the tumor peripherygreater than or equal to 90 (P = 0.007). The authors suggested a significant survival advantage, the subsequent 123
  • 16. 328 J Neurooncol (2008) 89:313–337published report did not. The final report of Selker et al. suggesting that there appeared to be a survival advantagedescribed this randomized multi-center comparison of favoring patients eligible for stereotactic radiosurgery,surgery, EBRT and BCNU (n = 137) versus surgery, primarily based on the inclusion of a subgroup with aEBRT, BCNU and I-125 brachytherapy boost (n = 133) in higher KPS. Subsequently, Lustig et al. applied the entrynewly diagnosed malignant glioma (299 total patients, with criteria for the RTOG 93-05 randomized trial of EBRT plus270 (90%) in the valid study group) [51]. The median SRS versus EBRT alone, to a previous randomized RTOGsurvival, with all pathologies included, for surgery, EBRT trial not involving SRS using RTOG RPA analysis [55].and BCNU (control) was 14.7 months compared to They reported that no significant difference could be17.0 months for surgery, EBRT, BCNU and (125)-I demonstrated between the two groups comparing the SRSbrachytherapy (P = 0.101). In the GBM only group eligible versus the SRS ineligible groups, supporting the(n = 230) the median survival was 14.5 for control outcome of the trial subsequently reported by Souhmai(n = 107) and 16.0 months for the brachytherapy group et al. [56]. These reports highlight the importance of(n = 123), (P = 0.169). As in most previous studies, age, careful interpretation of individual studies and the need toKPS, and pathology were all independent predictors of avoid extrapolation of the results to patient groups notmortality. Incorporating an adjustment for these variables specifically studied in a given trial.in both stratified and Cox proportional hazard models The results of the RTOG 93-05 trial were reported byfailed to demonstrate any statistically significant differ- Souhami et al. and are outlined in the evidentiary table forences in survival between these two treatment groups. The stereotactic radiosurgery [56]. This prospective multi-cen-authors concluded that no long-term survival advantage ter randomized trial recruited 203 patients. Seventeenwas demonstrated with the addition of (125)-I brachy- patients were excluded from final analysis including seventherapy to surgery, EBRT and BCNU in patients with who were randomized to SRS but had tumor treatmentnewly diagnosed malignant glioma (see Evidentiary diameters greater than 40 mm at the time of SRS. TenTable 7 for further details on brachytherapy) [52, 53]. additional patients were excluded based on histology (n = 3), refusal or withdrawal (n = 4), multifocal tumorStereotactic radiosurgery (n = 1), prior chemotherapy (n = 1) and failure to record KPS (n = 1), leaving 186 patients for evaluation. Ninety-Stereotactic radiosurgery is used to provide a single seven were randomized to EBRT alone and eighty-nine tofraction of radiation utilizing computer assisted stereo- EBRT plus SRS. Both groups received IV BCNU. Mediantactic technique. A series of encouraging reports initially survival was 13.6 in the EBRT group and 13.5 in EBRTdescribed the use of radiosurgery as a focal radiation plus SRS (P = 0.57) with no significant difference in twodose boost in conjunction with fractionated external and three survival rates or quality of life measures. Thebeam radiotherapy. Selected studies are detailed in the authors conclude that stereotactic radiosurgery followed byEvidentiary Table 8 (Stereotactic Radiosurgery). These EBRT and BCNU does not improve outcome in patientsstudies represented early trials in determining the safety with newly diagnosed GBM.and feasibility of this technique and generally compared Despite a relatively large number of preliminary trialsstudy outcome to historical controls from the RTOG suggesting a survival benefit, currently randomized dataRPA data. Reported median survivals for GBM ranged does not support the use of stereotactic radiosurgery as afrom 10 to 20 months and 2-year survivals ranged from routine addition to the initial management of glioblastoma.20% to 40%. Reoperation following these combined Selected patients may benefit but the specific characteris-radiotherapy technique ranged from 10 to 30%. Essen- tics of this group have yet to be identified (see Evidentiarytially all of these authors acknowledged the limitations of Table 8 for further particulars on stereotactic radiosurgery)their studies and given the limited toxicity observed, [57–66].indicated the need for a randomized prospective study toevaluate the role of SRS in newly diagnosed malignantglioma. Summary and key issues for future investigation The question of selection bias is of concern as noted forbrachytherapy trials and has been addressed. Initially, Review of the literature published to date provides clearCurran et al. applied previously used selection criteria for and consistent class I data supporting the role of adjuvantSRS (KPS [ 60, tumor diameter of 4.0 cm or less, and radiation therapy in the treatment of glioblastoma. Earlysuperficial location) to patients entered in a separate trial studies provide evidence comparing radiation therapy tonot involving SRS [54]. They found that the median sur- supportive care, chemotherapy and combinations of ther-vival for SRS eligible patients was 14.4 months versus apy and virtually all conclude that arms that included11.7 months for SRS ineligible patients (P = 0.047) radiation therapy had enhanced survival.123
  • 17. J Neurooncol (2008) 89:313–337 329Evidentiary Table 7 BrachytherapyFirst author/ Study description Data class ConclusionReferenceLamborn et al./ [49] Survival analysis of single institution data II Multivariate analysis (Cox) indicated significant effect of: accumulated from eight clinical Chemotherapy Hazard Ratio 0.60 P 0.001 prospective trials on 832 newly Extent of resection Hazard Ratio 0.75 P 0.001 diagnosed GBM (based on 776 with complete data) KPS Hazard Ratio 0.97 P 0.001 Analysis using Cox proportional hazards Age Hazard Ratio 1.03 P 0.001 modeling and recursive partitioning Brachytherapy Hazard Ratio 0.60 P 0.001 analyses The inclusion of brachytherapy in the overall treatment had a significant effect on survival and altered the results of the recursive partitioning analysis This is a retrospective analysis of previous reported randomized dataChang CN et al., J Comparative study of 28 newly diagnosed III Median survival: Neurooncol 2003 GBM treated postop with EBRT and EBRT plus brachytherapy 19.5 months [52] brachytherapy (high dose rate HDR) EBRT 12.5 months (P-value not stated) and 28 controls treated without the addition of brachytherapy Two year survival: Selection based on patient or physician EBRT plus brachytherapy 61% preference EBRT 28% (P = 0.12) All deemed eligible for brachytherapy: Median survival by RTOG RPA Class: Unilateral, supratentorial, less than 6 cm, Class 3: 41.6 versus 21.2 months (P = 0.39) KPS over 60 without subependymal Class 4: 16.7 versus 12.1 months (P = 0.37) spread Class 5: 18.7 versus 10.6 months (P = 0.02) The authors felt that a trend in favor of brachytherapy was demonstrated but due to the small numbers only the comparison within RTOG Class 5 reached significance. The issues surrounding high-dose versus low-dose brachytherapy were discussed and a prospective study was proposedMayr, M. et al. Int J Retrospective review of 73 patients (67 III Median survival for newly diagnosed GBM was Oncol 2002 [53] evaluable) treated with brachytherapy 9.02 months Includes 17 newly diagnosed GBM and For patients with a glioblastoma multiforme, median 28 recurrent survival from diagnosis and implant was 15.7 and 9.3 months respectively For patients with an anaplastic astrocytoma, median survival from diagnosis and implant was 39.5 and 9.2 months respectively Eleven patients (16%) developed radiation necrosis. Six patients (9%) developed infections Age and histologic diagnosis were significant predictors of survival from diagnosis Age and KPS were independent predictors of time to failure after implant Certain characteristics, specifically younger age (55), and a higher KPS (C70), appear to be associated with longer survival after brachytherapy. Complication rate significant and must be taken into consideration when adding brachytherapy to other treatment regimens Data supporting the most common conventional dose of Several attempts to utilize altered fractionation schemesapproximately 60 Gy in 30 fractions of 2 Gy each are have been studied. Hyper-fractionated radiotherapy, with-ubiquitous. Studies looking at lower doses in conventional out significant acceleration in terms of delivery duration,fashion and higher doses in conventional fashion appeared has been explored in class I studies and failed to show aeither inferior or of no additional benefit. significant benefit. A roughly equivalent biological dose to 123
  • 18. 330 J Neurooncol (2008) 89:313–337Evidentiary Table 7 continuedFirst author/ Study description Data class ConclusionReferenceSelker et al./[51] Randomized multicenter comparison. I Brain Tumor Cooperative Group NIH Trial 87-01 trial to Newly diagnosed malignant glioma investigate the effect of implanted radiation therapy in (299 patients, 270 (90%) in valid study addition to surgery, EBRT and BCNU in newly group). Surgery, EBRT and BCNU diagnosed GBM (n = 137) versus Surgery, EBRT, Median survival (all pathologies included): Surgery, BCNU and (125)-I brachytherapy boost EBRT, BCNU (control) 14.7 months (n = 133) Surgery, EBRT, BCNU and (125)-I brachytherapy 17.0 months (P = 0.101) Median survival (GBM only, 230 patients): Surgery EBRT, BCNU (control) (n = 107) 14.5 months Surgery, EBRT, BCNU and (125)-I brachytherapy (n = 123) 16 months (P = 0.169) Age, KPS, and pathology were predictors of mortality Analysis incorporating an adjustment for these prognostic variables, using both stratified analysis and Cox proportional hazards models, failed to demonstrate any statistically significant differences in the cumulative proportion of patients surviving between the two treatment groups The authors concluded that no long-term survival advantage was demonstrated with the addition of I-(125) brachytherapy to surgery, EBRT and BCNU in patients with newly diagnosed malignant gliomaKoot et al./[47] Comparative study of two methods of III Median survival (for Age [ 50, KPS [ or = 70, non- brachytherapy applied to 84 patients midline): with newly diagnosed GBM treated in I-(125) group 17 months two different centers. All treated with Ir-(192) group 16 months EBRT. Control 10 months (no p value reported) Biopsy plus I-(125) implant (n = 45) and Resection plus Ir-(192) implant compared Volume: with Surgery plus EBRT (n = 18) I-(125) group–average volume 23 cm3 Ir-(192) group–average volume 48 cm3 Dose Rate: I-(125) group dose rate–permanent implants 2.5–2.9 cGy/h, temporary implants 4.6 cGy/h Ir-(192) group dose rate–temporary implants 44–100 cGy/h Reoperation (necrosis, tumor or both): I-(125) group–4 (9%) Ir-(192) group–7 (33%) The authors conclude that given the similar survival observed regardless of methodology of brachytherapy that dose rate does not play a significant role in the effect of brachytherapy in the treatment of malignant glioma. The uncontrolled nature of this study complicates the interpretation of the results but there does appear to be a higher rate of necrosis observed in the higher dose rate delivery groupthe conventional fractionated dose of 60 Gy (72 Gy in 60 treatment and hence without a clear benefit in survival is notfractions) appeared the best choice in large hyper-frac- recommended. Hypo-fractionated radiotherapy has beentionated series that looked at both higher and lower doses studied in several class I level studies in selected older or[10]. The additional effort in delivering twice or three times more poorly performing patients and has appeared to do asdaily treatment is generally felt to increase the difficulty of well as conventional fractionation [19, 31]. Despite this a123
  • 19. J Neurooncol (2008) 89:313–337 331Evidentiary Table 7 continuedFirst author/ Study description Data class ConclusionReferenceVidetic et al./[48] Single center stratification of GBM III Two-year survivals and median survival for implanted patients treated with surgery, EBRT GBM patients compared to the RTOG database: and I-(125) brachytherapy at initial Class III 74% versus 35% and 28 months versus diagnosis by RPA survival class 17.9 months focusing on the relationship between Class IV 32% versus 15% and 16 months versus implant volume and survival and 11.1 months whether volume acted as a prognostic variable within each RPA class Class V/VI 29% versus 6% and 11 months versus 8.9 months Review of 52 (of 53) GBM patients Mean implanted tumor volume was 15.5 cc (range 0.8–78) Class III–12, Class IV–26 Plotting survival as a function of 5-cc TV increments Class V–13 suggested a trend toward poorer survival as the Class VI–1. Mean age 57.5 years (range implanted volume increases 14–79). Effect of implanted volume on survival by RPA class: Median KPS 90 (range 50–100) Class III no significant difference observed Median follow-up 11 months Class IV, marginally significant difference at 10 cc (P = 0.05) Class V/VI, marginally significant difference at 20 cc (P = 0.06) The authors concluded that for GBM patients, an inverse relationship between implanted tumor volume and median survival was suggested but the prognostic effect disappeared within each RPA class suggesting that any patient meeting size criteria for brachytherapy be considered for implantationLaperriere et al./[50] Randomized prospective trial of 140 I Median survival: patients with newly diagnosed GBM EBRT 13.2 months Two Groups: EBRT plus brachytherapy 13.8 months (P = 0.49) EBRT 50 Gy in 25 fractions (n = 69) Improved survival associated with either chemotherapy or EBRT 50 Gy in 25 plus I 125 reoperation at progression (P = 0.004) or KPS greater brachytherapy to 60 Gy (n = 71) than or equal to 90 (P = 0.007) The authors concluded that the addition of brachytherapy did not demonstrate a statistically significant improvement in survival over EBRT alone in the initial management of newly diagnosed GBMSneed et al./[44] Randomized single-institution study of III for Evaluation of effect of adjuvant interstitial hyper-thermia hyper-thermia in addition to surgery, brachytherapy (HT) in patients with glioblastoma undergoing EBRT, brachytherapy in newly- data brachytherapy boost after conventional radiotherapy diagnosed GBM Median survival: 35 patients treated with hyper-thermia Surgery, EBRT and brachytherapy 19.0 months versus 33 without Surgery, EBRT, brachytherapy and hyper-thermia 21.2 months (P = 0.02) Two-year Survival: Surgery, EBRT and brachytherapy 15% Surgery, EBRT, brachytherapy and hyper-thermia 31% (P = 0.045) The authors concluded that adjuvant interstitial brain HT, used with brachytherapy boost significantly improved survival of patients with focal glioblastoma. This study did not randomize patients to brachytherapylarge and inclusive trial with a hypo-fractionated arm has accrual and concerns for a more inclusive populationnot been performed. Concerns regarding long term sequelae [19, 28]. Accelerated fractionation has also failed to show awith very limited fractionation schemes has lead to poor significant benefit in class I studies [39, 40]. 123
  • 20. 332 J Neurooncol (2008) 89:313–337Evidentiary Table 7 continuedFirst author/ Study description Data class ConclusionReferenceSneed et al./[45] Retrospective review of newly diagnosed III Retrospective review undertaken to examine the influence GBM treated with EBRT and I-(125) of age on the survival of patients undergoing brachytherapy (n = 159) brachytherapy in newly diagnosed GBM Brachytherapy doses ranged from 35.7 to 66.5 Gy (median, 55.0 Gy) at 0.30 to 0.70 Gy per hour (median, 0.43 Gy/h) Median survival 19 months Reoperations were performed in 81 patients (51%) Univariate and multivariate analyses showed that age was the most important parameter influencing survival (P 0.0005)Wen et al./[43] Prospective non-randomized protocol and II Median survival: review of 56 newly-diagnosed Brachytherapy 18 months glioblastoma patients Control 11 months (P 0.0007) Surgery, EBRT, and (125)-I Two-year survival: brachytherapy (additional 50 Gy to the tumor bed). Compared to 40 matched Brachytherapy 34% controls Control 12.5% (P 0.0004) Thirty-six patients (64%) re-operation for symptomatic radiation necrosis (median interval 11 months 3 to 42 months). Median survival after reoperation 22 months versus 13 months without (P 0.02) Radiographic progression in brachytherapy group: Local 35% Marginal or Distant progression 65% The authors conclude that brachytherapy may prolong survival and improve local tumor control in the initial treatment of selected patients with glioblastoma. The study represents prospective data collected and compared with a matched control group The treatment volume for external beam radiotherapy is margin––there is little class I data addressing the issue ofperhaps the most incompletely studied question despite appropriate volume in glioblastoma or malignant glioma.clear patterns of care being established. Most studies sup- The addition of boost doses of radiation therapy and inporting the role of adjuvant radiation therapy used whole particular both brachytherapy and stereotactic radiosurgerybrain radiotherapy, a technique that is not recommended as have been extensively studied in recent years. Largea standard approach today. One class I/II study compared a institutional class III trials suggested potential benefit forwhole brain dose of 40 Gy plus a boost of 18 Gy to an brachytherapy and lead to class I randomized trials [43–approach using local fields for 56 Gy and found no dif- 46]. Unfortunately, class I trials did not show the promisingference in outcome at 2 years [18]. In addition BTCG trial results of the previous more selected and uniform institu-8001 allowed a change during the protocol accrual to limit tional series and failed to show a benefit to brachytherapythe whole brain dose to 43 Gy followed by a boost and [50, 51]. Similarly, several large and controlled institu-found no difference compared to the traditional whole tional and non-randomized multi-institutional trialsbrain dose of 60 Gy [17]. This taken along with class III suggested the potential of benefit for stereotactic radio-data showing that more than 80% of recurrences occurred surgery. Despite this promise the test of a randomized trialwithin 2 cm of the resection and enhancing volume bed via the RTOG 93-05 failed to show a survival benefit forsupport the strategy of deleting whole brain radiotherapy. dose escalation achieved through stereotactic radiosurgeryDespite this generally accepted practice of treating the [56]. These techniques are therefore not recommended as aedema volume with an approximately 2 cm margin fol- standard component of therapy for glioblastoma or malig-lowed by a boost to the enhancing volume with 1–2 cm nant glioma.123
  • 21. J Neurooncol (2008) 89:313–337 333Evidentiary Table 8 Stereotactic radiosurgeryFirst author/ Study description Data class ConclusionReferenceSouhami et al./[7] Randomized prospective trial of I This study investigated the effect of stereotactic radiosurgery 203 patients with newly (SRS) added to conventional external beam radiation therapy diagnosed supratentorial GBM (EBRT) with carmustine (BCNU) on the survival of patients (tumor less than or equal to with newly diagnosed GBM 40 mm maximum cross section Median survival: after surgery) Postop SRS plus SRS plus EBRT/BCNU 13.5 months (95% CI EBRT (60 Gy) plus BCNU 11.0–14.8 months) (n = 89) versus EBRT plus BCNU (n = 97) SRS dose EBRT/BCNU 13.6 months (95% CI volume dependent (range 15 to 11.2–15.2 months) P = 0.57 24 Gy) Median followup There were also no significant differences in 2- and 3-year 61 months survival rates and in patterns of failure between the two arms 17 patients excluded consisting of Quality of life deterioration and cognitive decline equivalent. No 10 for path, patient refusal or difference in quality-adjusted survival between the arms protocol violation and 7 for tumor The authors concluded that stereotactic radiosurgery followed by size greater than 40 mm at time of EBRT and BCNU did not improve the outcome, quality of life SRS or cognitive function in patients with newly diagnosed GBMCho, K. H. et al. Retrospective review of 24 III This study compared single dose or fractionated stereotactic Technol Cancer patients with newly diagnosed boosted therapy plus EBRT in newly diagnosed GBM Res Treat 2004 GBM treated with EBRT plus a Overall median survival 16 months [64] stereotactic boosted therapy Overall 1 year survival rate 63% Fourteen patients (58%) were Overall 2 year survival rate 34% treated with stereotactic radiosurgery (SRS) and 10 patients Median survival: (42%) with fractionated RTOG Class 3 28.3 months (expected 11.1) stereotactic radiotherapy (FSRT) RTOG Class 4 10.3 months (expected 8.9) RTOG Class 5/6 6.0 months (expected 4.6) Survival predicted by age, extent of surgery, re-operation and the RTOG RPA class The authors concluded in this non-randomized retrospective study that the observed median survival of 16 months was superior to that expected by historical RTOG RPA controls with similar results with either SRS or FSRT (possibly with less complication in the FSRT group) and that further study is warrantedLustig et al./ [55] Study applying the entry criteria of II Comparison of Median survival by RTOG RPA Class for patient the RTOG 93-05 trial (Souhami either eligible or ineligible for SRS trial: et al 2004) to the patient Median survival SRS eligible enrolled in the RTOG 90-06 RTOG RPA Class 3 16.8 months trial comparing 60 Gray versus 72 Gray in patients with GBM RTOG RPA Class 4 12.0 months to evaluate possible selection RTOG RPA Class 5 8.3 months bias of the SRS entry criteria RTOG RPA Class 6 1.7 months 599 total patients. 137 Eligible and Median survival SRS ineligible 372 Ineligible for 93-05 Radiation Therapy Oncology Group (RTOG) RTOG RPA Class 3 16.8 months (P = NS) Recursive partitioning analysis RTOG RPA Class 4 10.8 months (P = 0.042) (RPA) was used to evaluate for RTOG RPA Class 5 7.2 months (P = 0.09) differences RTOG RPA Class 6 2.7 months (P = 0.2) The authors conclude that there does not appear to be a selection bias performing a randomized study on patients eligible for stereotactic radiosurgery, supporting the validity of a randomized study of the effects of stereotactic radiosurgery in newly diagnosed GBM This is review of previous reported randomized data 123
  • 22. 334 J Neurooncol (2008) 89:313–337Evidentiary Table 8 continuedFirst author/ Study description Data class ConclusionReferenceNwokedi, E. C., Retrospective review of 82 III Retrospective review of the impact of SRS on patients treated for et al. patients with GBM. 64 included GBM Neurosurgery in review Median survival: 2002 [65] 33 treated with EBRT and 31 EBRT 13 months treated with EBRT plus SRS (10– EBRT plus SRS 25 months (P = 0.03) 28 Gray) Predictors of overall survival by Cox regression analysis included: Miniumum followup of 1 month age, KPS and SRS reported No acute Grade 3 or Grade 4 toxicity was encountered The authors conclude that SRS in conjunction with surgery and EBRT significantly improved survival but deferred to forthcoming randomized studyShrieve, D. C., et al. Retrospective review of 78 III Median survival 19.9 months J of Neurosurg patients treated with EBRT and One year survival 88.5% 1999 [66] SRS boost Two year survival 35.9% Age, RPA class significant in univariate analysis Age significant in multivariate analysis Reoperation rate 54.8% The authors conclude that SRS appears to add a significant survival advantage and support a randomized trialKondziolka, D., et al Retrospective review of 109 III For newly diagnosed (SRS plus EBRT): Neurosurgery patients involving SRS in Median survival: GBM 20 months (s.d. 2.6) range 5 to 76 months, 1997 [61] additional to EBRT in malignant AA 56 months (s.d. 8.9) range 9 to 93 months glioma management Two year survival: GBM 41%, AA 88% Included n = 45 newly diagnosed Reoperation rate: GBM 19%, AA 23% GBM and n = 21 AA The authors conclude that SRS appears promising and call for a randomized triaLarson, D. A., et al. Retrospective review of 189 III Median survival: Int J Radiat Biol patients either primary or GBM Phys 1996 [62] recurrent malignant glial tumor Brachytherapy eligible 21.5 months patients treated with SRS as a portion of their overall Brachytherapy ineligible 10 months (P = 0.01) treatment. Includes 41 newly AA diagnosed GBM and 16 AA Brachytherapy eligible 24 months Patients stratified by whether they Brachytherapy ineligible 24 months (P = NS) would be eligible for brachytherapy in previous Tumor grade, age, KPS, smaller volume, unifocal tumor all protocols correlated with prolonged survival The authors conclude that bias in patient selection is concerning and support need for randomized trialSarkaria, J. N., et al. Combined retrospective analysis III Stratified by and Compared to RTOG RPA analysis: Int J Radiat Biol of data from three centers SRS boost Phys 1995 [63] (Masciopinto et al., Buatti et al., RTOG RPA Class 3 38.1 months Shrieve et al.) RTOG RPA Class 4 19.6 months 115 patients with newly diagnosed malignant glioma (96 GBM and RTOG RPA Class 5/6 13.1 months 19 AA) RTOG RPA Historical Control RTOG RPA Class 3 17.9 months RTOG RPA Class 4 11.1 months RTOG RPA Class 5/6 8.9 months Overall P-value 0.001. The authors conclude that the addition of SRS to EBRT in patients treated with malignant glioma appears to improve survival and support a randomized trial123
  • 23. J Neurooncol (2008) 89:313–337 335Evidentiary Table 8 continuedFirst author/ Study description Data class ConclusionReferenceMasciopinto, J. E., Retrospective review of 31 III Median survival 9.5 months et al. J Neurosurg patients with newly diagnosed Two year survival 37% 1995 [57] GBM treated with EBRT plus The authors conclude that due to limited response and local SRS recurrence that the role of SRS in malignant glioma be Follow report of Mehta et al. 1994 carefully considered in selected patients until further study belowGannett, D., B. et al. Retrospective review of 30 III Overall median survival 13.9 months Int J Radiat Biol patients including 17 newly One year survival 57% Phys 1995 [58] diagnosed GBM and 10 AA Two year survival 25% No significant toxicity reported Reoperation rate 10% The authors concluded that SRS could be used to provide safe and feasible technique for dose escalation in the primary management of unselected malignant glioma and call for a randomized studyBuatti, J. M., et al. Retrospective review of 11 newly III Median survival 17 months Int J Radiat Biol diagnosed patients (6 GBM and Maximum radiosurgical volume 22.5 cm3 Phys 1995 [59] 5 AA) treated with EBRT and All patients had local progression within one year of treatment SRS The authors note the need to define appropriate patients for boost techniqueMehta, M. P., J. Retrospective review of 31 III Median survival 10.5 months et al. Int J Radiat patients with newly diagnosed One year survival 38% Biol Phys 1994 GBM treated with EBRT and Two year survival 28% [60] SRS (of a total of 53 newly diagnosed GBM patients in Authors suggest that this may demonstrate improved 2 year same time period) survival compared to RTOG RPA 2 year survival of 9.7% (P 0.05) but that the improvement in broadly selected GBM is difficult to determine Reported 13% symptomatic necrosisCurran et al./[54] Study applying SRS treatment II Comparison of Median Survival by RTOG RPA Class for patient criteria (KPS [ 60, 4.0 cm or either eligible or ineligible for SRS trial: less, and superficial) to the Median Survival Eligible 14.4 months Median Survival Ineligible patients enrolled in RTOG 83- 11.7 months (P = 0.047) 02 trial (Phase I/II dose Multivariate analysis indicated age, KPS, path and SRS eligibility escalation) all predictive of increased survival 778 total patients 89 (11%) The authors conclude that there appeared to be a survival determined to be eligible for SRS advantage favoring patients eligible for stereotactic radiosurgery, primarily based on inclusion of a subgroup of higher KPS This is a review of previously reported randomized data Review of this data leads to the conclusion that radiation volume as identified on imaging with a 1–2 cm margin.therapy should be recommended as standard therapy for Although there is minimal Class I support for this, theglioblastoma and malignant glioma as supported by con- preponderance of evidence supports this approach andsistent class I data. Patients with good prognosis can there is no clear benefit of larger whole brain fields. Studiesconfidently be treated with conventional doses of 60 Gy in addressing the appropriate volume in systematic fashion30 fractions as supported by the body of the literature. are needed. The role of dose escalation with brachytherapyConsideration for hypo-fractionated regimens especially in and radiosurgery is limited and not supported as a standardthe setting of poor prognosis is very reasonable and is approach.supported by the literature in class I data. Other alteredfractionation schemes are not supported outside a study Acknowledgements We wish to acknowledge Stephen Haines, MD, Jack Rock, MD, and Tom Mikkelson, MD for their review andsetting. Local fields are generally used to treat the tumor consultations regarding on this work. The authors also wish to express 123
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