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Radiation therapy of pathologically confirmed newly diagnosed ...

  1. 1. INVITED MANUSCRIPT Radiation therapy of pathologically confirmed newly diagnosed glioblastoma in adults John Buatti Æ Timothy C. Ryken Æ Mark C. Smith Æ Penny Sneed Æ John H. Suh Æ Minesh Mehta Æ Jeffrey J. Olson Received: 9 January 2008 / Accepted: 19 May 2008 Ó Springer Science+Business Media, LLC. 2008 Recommendations Level 1 Radiation therapy is recommended for the treatment of newly diagnosed malignant glioma in adults. Treatment schemes should include dosage of up to 60 Gy given in 2 Gy daily fractions that includes the enhancing area. Hypo-fractionated radiation schemes may be used for patients with a poor prognosis and limited survival without compromising response. Hyper-fractionation and accelerated fractionation have not been shown to be superior to conventional fractionation and are not recommended. Brachytherapy or stereotactic radiosurgery as a boost to 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 2 It is recommended that radiation therapy planning include a 1–2 cm margin around the radiographically defined T1 contrast-enhancing tumor volume or the T2 weighted abnormality on MR imaging. Rationale Although radiation therapy has been a standard therapy for the treatment of malignant glioma for more than 25 years there remains controversy as to the optimal way to deliver this ther- apy. Because of several randomized trials in the late 1970s and early1980sthatshowedabenefitwithradiationtreatmentalong with retrospective series showing that there was a high rate of local recurrence; the stage was set for dose escalation to be studied. Dose escalation in conventional, hyper-fractionated, accelerated and hypo-fractionated radiotherapy was evaluated. Increased local dose was also evaluated including stereotactic radiosurgery and brachytherapy. Generally survival has been used as the endpoint for clinical trials, but increasing interest in quality of life issues has yielded additional information par- ticularly in the older patients and poor prognostic groups. J. Buatti Department of Radiation Oncology, University of Iowa, Iowa City, IA, USA T. C. Ryken Department of Neurosurgery, University of Iowa College of Medicine, Iowa City, IA, USA M. C. Smith Department of Radiation Oncology, University of Iowa Hospitals and Clinics, Iowa City, IA, USA P. Sneed Department of Radiation Oncology, University of California, San Francisco, CA, USA J. H. Suh Department of Radiation Oncology, Cleveland Clinic Foundation, Cleveland, OH, USA M. Mehta Department of Radiation Oncology, University of Wisconsin, Madison, WI, USA J. J. Olson (&) Department of Neurosurgery, Emory University School of Medicine, 1365B Clifton Rd., NE, Ste. 6200, Atlanta, GA 30322, USA e-mail: jeffrey.olson@emoryhealthcare.org 123 J Neurooncol (2008) 89:313–337 DOI 10.1007/s11060-008-9617-2
  2. 2. This review focused on the issue of whether radiation therapy is of benefit in the management of patients diagnosed with malignant glioma. In addition, issues relating to the delivery of this therapy are reviewed, with emphasis on issues relevant to neurosurgeons involved in the treatment of patients diagnosed with malignant glioma, including brachytherapy and radiosurgery. The literature on radiation sensitizers and proton beam radiotherapy was deferred but is reviewed thoroughly in the excellent systematic review of radiation therapy for malignant glioma by Laperriere et al. for the Neuro-oncology Disease Site Group of the Cancer Care Ontario Program available through the National Guideline Clearinghouse (www.guideline.gov) [1]. Search criteria A National Library of Medicine literature search was undertaken including the period from 1966 through 2005 initially using the MESH subject heading astrocytoma gen- erating a broad base of studies. Titles and abstracts were reviewed with attention to those titles including radiation therapy, radiosurgery, or radioactive implant. Secondary searches crossing astrocytoma with radiation and radiation therapy were undertaken. Bibliographies of selected papers were reviewed for additional references of relevance. Articles were selected if they addressed issues of radi- ation therapy of malignant gliomas, dose considerations, volume considerations or dose escalation techniques such as radiosurgery or brachytherapy. Articles were preferen- tially reviewed if they contained randomized or prospective data. Randomized controlled trials were given preference as Class I data. Cohort-matched or case–control studies were given secondary consideration as Class II information and institutional reviews with comparisons to historical controls were categorized as Class III data. Scientific foundation Role of postoperative radiation therapy Interest in radiation therapy for primary brain tumors led to a series of randomized, multi-institutional studies, includ- ing the widely quoted studies by the Brain Tumor Study Group (BTSG) in the late 1970s and early 1980s. In some instances these studies provide Class I data addressing the role of radiation therapy in the management of newly diagnosed malignant glioma and demonstrate that it is effective at prolonging the life of patients with malignant glioma compared to no treatment. In general, these trials compared surgery, radiation therapy and chemotherapy alone or in various combinations. The first randomized study was reported by Shapiro in 1976 and randomized patients to surgery followed by carmustine (BCNU) and vincristine chemotherapy versus surgery followed by identical chemotherapy along with 45 Gy whole brain radiotherapy and 15 Gy boost dose to the side ipsilateral to the lesion [2]. The results showed a median survival of 11.1 months in the radiotherapy arm compared to 7.5 months in the chemotherapy only arm. Despite the apparent survival advantage the difference was not statistically significant possibly because only 33 patients were randomized, three of whom withdrew prior to completing therapy. In addition, the groups were not 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, which further supports the role of radiation therapy. The report also noted that five patients in the radiotherapy group had multi-centric or bilateral involvement versus only 2 in the chemotherapy alone group. In 1978, the first of the BTSG studies addressing these issues was reported by Walker et al. [3]. There were 303 patients with malignant glioma randomized to one of four study arms after surgical management. These included a control of best supportive care alone after surgery, che- motherapy alone with BCNU, radiation therapy alone with whole brain radiotherapy to a dose of 50–60 Gy, and a combination of BCNU with radiotherapy (identical doses and delivery). Of the entire study group 73% were felt to have been valid for analysis (valid study group), including pathological confirmation and treatment according to the protocol. The authors also reported an ‘‘adequately treated’’ group that received at least the prescribed dose of radiation and at least two of the planned courses of BCNU chemo- therapy. Analysis showed a significant advantage for those groups receiving radiation therapy compared to those 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, 9.4 months in the radiotherapy alone group and 10.1 month in the group receiving both chemotherapy and radiation. The results of the later three were all statistically signifi- cant when compared to the surgery alone group. This provides Class I data supporting a role for radiation therapy. The follow-up BTSG study reported in 1980 random- ized 467 patients with malignant glioma to semustine (CCNU) chemotherapy alone, radiotherapy alone, radio- therapy plus CCNU or radiotherapy plus BCNU [4]. This study again confirmed a significant advantage for the groups receiving radiotherapy. The radiotherapy in this trial was better controlled and included specification of 60 Gy in 6–7 weeks. The results in the ‘‘valid study’’ group that fulfilled protocol criteria indicated a median survival 314 J Neurooncol (2008) 89:313–337 123
  3. 3. of 6 months in the CCNU alone arm, 9 months with radiotherapy alone, 12.8 months with BCNU plus radio- therapy and 10.5 months with CCNU plus radiotherapy. Statistical analysis indicated a significant survival advan- tage in radiotherapy containing arms over chemotherapy alone. This provided additional Class I data supporting the role for radiotherapy. A randomized study in Europe was reported in 1981 by Kristiansen, et al. [5]. The study was a three arm ran- domized, placebo controlled trial following surgical management comparing best supportive care, radiotherapy alone (with placebo) and radiotherapy combined with concomitant bleomycin. The radiation in this trial was 45 Gy to the whole brain. Over the course of the study, 118 patients were randomized into the three arms with reported median survivals of 5.2 months for the best supportive care and 10.8 months for both the combined bleomycin/radio- therapy and radiotherapy alone groups. The authors indicate this was statistically significant but do not provide statistical detail for review. The randomized trial published by Sandberg-Wolheim et al. was conducted in Sweden and included 171 patients that were randomized to receive procarbazine, CCNU and vincristine (PCV) alone or in combination with 50 Gy to the whole brain and an additional 8 Gy to the ipsilateral hemisphere for a total of 58 Gy [6]. The analysis included 139 patients in the ‘‘valid study’’ group. In this group the median survival for the chemotherapy only group was 11.8 months versus 16.5 months with the addition of radiotherapy (P = 0.01). The trial showed that the addition of radiotherapy was advantageous and particularly so in those younger than 50 years of age (median survival 19.3 months versus 30.5 months, P = 0.037). Finally, in a systematic review of these six randomized studies addressing the issue of survival advantage created by postsurgical external beam radiotherapy, Laperriere et al., detected a significant survival benefit [7]. The risk ratio of 0.81 (P 0.00001) indicates a reduction in risk of dying over the course of the studies in patients receiving radiotherapy as opposed to not receiving it. Thus, even though some of the studies contained smaller numbers and did not achieve individual statistical significance, the combined data favors a definite survival advantage with external beam radiotherapy (see Evidentiary Table 1 for further details on the role of postoperative radiation ther- apy) [8]. Dose Review of the literature reveals several randomized trials addressing the optimal dose of radiotherapy for patients with malignant glioma. Following the initial success of the BTCG studies, trials using higher total radiotherapy doses were undertaken. However, no clear benefit to escalation has been demonstrated. A randomized trial of 443 patients reported by the Medical Research Council in the United Kingdom com- pared whole brain radiotherapy dosage of 45 Gy in 20 fractions to 60 Gy in 30 fractions for patients with newly diagnosed malignant glioma, as described by Bleehen et al. [9]. A two to one randomization scheme placed more patients in the higher dosage scheme. The 1-year survival rates were 29% for the 45 Gy arm and 39% for the 60 Gy arm. The 18 month-survival rates were 11% and 18%, respectively and both comparisons were statistically sig- nificant (P = 0.04). This study provides Class I data supporting a dose of 60 Gy compared to 45 Gy. In the combined Radiation Therapy Oncology Group (RTOG) and Eastern Cooperative Group (ECOG) trial reported by Nelson et al., 626 patients with newly diag- nosed malignant glioma were randomized to four arms that included 60 Gy to the whole brain (141 patients), 60 Gy to the whole brain with a 10 Gy boost to the tumor (103 patients), 60 Gy with carmustine (156 patients) and 60 Gy with semustine and dacarbazine (138 patients) [10]. The median survival for the 60 and 70 Gy arms was reported as 9.3 and 8.2 months. No significant difference in median survival was found between any of the treatment arms. This provides Class I data that a dose above 60 Gy is not ben- eficial (see Evidentiary Table 2 for further particulars on the dosage of radiation) [11–13]. Volume Despite the propensity of early whole brain radiotherapy studies, the choice for volume of radiation delivery has evolved to a more limited field based primarily on natural history studies demonstrating a tendency for local recur- rence [14–16] and Class II data suggesting a lack of benefit for whole brain radiotherapy compared to more limited fields. A high percentage of progressive disease is found within 1–2 cm of the initial treatment region. Early studies utilized whole brain radiotherapy; however, given this information and the advances in neuroimaging, recent years have seen a shift away from utilizing whole brain fields to the use of regional fields with margins around enhancing disease, generally on the order of 1–2 cm. Randomized studies addressing the volume of radio- therapy delivery have been limited. Shapiro et al. described the BTCG 8001 study in which 571 patients were ran- domized into three chemotherapy regimens [17]. In the early phase of the trial, patients received 60 Gy whole brain radiotherapy. In the later phases, the protocol was modified and patients received 43 Gy whole brain radio- therapy and an additional 17 Gy focused on the enhancing volume plus a 2 cm margin. After analysis there was no J Neurooncol (2008) 89:313–337 315 123
  4. 4. difference in survival between the two different radio- therapy regimens. Although this was a randomized study, it was not specifically designed to address the issue of radiotherapy delivery. Therefore there is only Class II data supporting the role of limited field therapy. Kita et al. published the results of their randomized trial in which patients received either 40 Gy whole brain radiotherapy in 20 fractions followed with a local boost of 18 Gy in nine fractions, giving a total dose of 58 Gy, or 56 Gy in 28 fractions targeted to the enhancing tumor Evidentiary Table 1 Postoperative external beam radiation First author/ Reference Study description Data class Conclusion Laperriere et al./[7] Systematic review of randomized trials Six randomized studies identified addressing the role of postoperative external beam radiotherapy in newly diagnosed malignant glioma following a surgical procedure I Meta-analysis Pooled data detected a significant survival benefit favoring postoperative radiotherapy compared to no radiotherapy (risk ratio 0.81, 95% CI 0.74– 0.88, P 0.00001). No significant heterogeneity (v2 = 6.73, P [ 0.10) 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 regimen Sandberg-Wollheim et al./[6] Randomized study of PCV with and without EBRT (58 Gy total 50 WBRT plus 8 additional to hemisphere) for malignant glioma Overall 171 patients Valid study group 139 due to protocol violations PCV (n = 71) PCV plus EBRT (n = 68) I Overall median survival (n = 171): PCV 10.5 months PCV plus EBRT 15.5 months (P = 0.03) Valid Study Group (n = 139): PCV 11.8 months PCV plus EBRT 16.5 months (P = 0.01) Most significant advantage in the Valid Study Group in patients under 50 years of age Median survival 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 50 Kristiansen et al./[5] Randomized study of surgery, surgery plus EBRT (45 Gray whole brain) or surgery, EBRT and bleomycin 118 patients with Grade 3 and 4 astrocytoma Group 1 Surgery, EBRT and bleomycin (n = 45) Group 2 Surgery plus EBRT (n = 35) Group 3 Surgery alone (n = 38) II Median survival: Surgery 5.2 months Surgery plus EBRT 10.8 months Surgery plus EBRT and bleomycin 10.8 months (no P-value reported but authors state it was statistically significant between surgery alone and the two groups with EBRT) No data on extent of resection and no detail on statistical analysis Authors concluded that the addition of radiotherapy doubles survival in patients with malignant glioma over surgery alone 316 J Neurooncol (2008) 89:313–337 123
  5. 5. Evidentiary Table 1 continued First author/ Reference Study description Data class Conclusion Walker et al./[4] Randomized comparison of EBRT (60 Gray whole brain) and nitrosoureas for the treatment of malignant glioma following surgery Randomized 467 patients. 358 completed study and formed valid study group Four arms: CCNU, EBRT, EBRT plus BCNU, EBRT plus CCNU I Median survival: CCNU 6 months EBRT 9 months EBRT plus BCNU 12.8 months EBRT plus CCNU 10.5 months Statistical analysis indicated that all groups receiving radiotherapy were significant versus CCNU alone (P-values from0.001 to 0.016). No 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 glioma Walker et al./[3] Evaluation of BCNU and/or radiotherapy in the treatment of malignant glioma Randomized 303 patients to best supportive care, BCNU, EBRT, EBRT plus BCNU EBRT 50 to 60 Gray whole brain I Median survival: Surgery alone 4.25 months BCNU 6.3 months (P 0.002), EBRT 9.4 months (P 0.001), EBRT plus BCNU 10.1 months (P 0.006) 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 Radiologica: Oncology, Radiation, Physics, Biology 1978 [8] Randomized trial of 108 patients with GBM to surgery or surgery plus EBRT (45 Gy whole brain) 57 patients surgery only 51 patients surgery plus EBRT II Six month survival rates: Surgery alone 25% Surgery plus EBRT 64% (P 0.05) One year survival rates: 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 evidence Shapiro and Young/ [2] Randomized study of BCNU and Vincristine alone (n = 17) or with EBRT (n = 16) (60 Gy–4500 whole brain plus 1500 boost ipsilateral) II Median survival–no statistically significant difference demonstrated 7.5 months versus 11.1 months (favors the addition 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 J Neurooncol (2008) 89:313–337 317 123
  6. 6. volume [18]. The authors reported no significant difference in survival between the two groups. The 2-year survival was 43% for the whole brain group versus 39% for the local field group and 17% versus 27% at 4 years. The study consisted of a small number of patients (23 and 26 patients respectively). This is additional Class II data supporting more limited fields. Although using an accelerated fractionation scheme, the study of Phillips et al. randomized 68 older patients (median age 58–59 years) with newly diagnosed glioblas- toma to either conventional fractionated therapy of 60 Gy in 30 fractions over 6 weeks or to 35 Gy in 10 fractions of whole brain radiotherapy [19]. This study also demon- strated no significant difference in survival comparing 10.3 months for conventional fractionation versus 8.7 months for the 35 Gy whole brain radiotherapy group (P = 0.37). See Evidentiary Table 3 for further details on the volume of tissue radiated. Altered fractionation schedules A variety of altered fractionation schemes have been descri- bed in attempting to optimize fractionated radiotherapy treatment. Terminology has developed in attempt to describe these alterations and can be somewhat confusing as the techniques invariably have some overlap. The comparison is typically made to what may be loosely defined as a con- ventional dose of approximately 60 Gy given in 30 fractions of 2 Gy over 6 weeks. Compared with conventional radio- therapy, hyper-fractionated radiotherapy is generally given to a higher total dose over a similar overall treatment time using multiple small fractions daily. The theoretical advan- tage is the ability to deliver a higher dose without increased toxicity, because of the smaller fraction size. The theoretical advantage of hypo-fractionation is that a shorter overall treatment time should enable better control of the tumor. In the most extreme case of hypo-fractionation, single fraction radiosurgery, toxicity is limited bytreating a smaller volume. Accelerated radiotherapy refers to a reduction in overall treatment time by delivering multiple daily doses closer to the usual size fraction to a similar overall dose. The basic advantage of accelerated treatments is to reduce overall treatment time, again assuming that acceptable efficacy and toxicity are obtained. A series of studies are reviewed below using various combinations of altered therapy. These include hyper- Evidentiary Table 2 Dose First author/Reference Study description Data class Conclusion Bleehen and Stenning/[8] Randomized 443 patients to 45 Gy in 20 fractions or 60 Gy in 30 fractions. Patients were randomized in a 2:1 ratio I Statistically significant difference correlating to an improvement in median survival of 2 months in the 60 Gy arm (P = 0.04) Nelson et al. NCI Monogr. 1988 [12] 626 patients randomized to 4 study arms: 60 Gy to whole brain; 60 Gy to whole brain plus a 10 Gy boost; 60 Gy plus carmustine 60 Gy plus semustine and dacarbazine I No statistically significant differences in survival for any of the 4 arms Chang et al. Cancer 1983 [11] Randomized controlled trial of RTOG and ECOG. Four study groups 60 Gy whole brain radiotherapy, 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, I No significant improvement in survival with the 10 Gy boost when compared to 60 Gy whole brain alone Walker MD Int J Radiat Oncol Biol Phys 1979 [13] Pooled data from randomized BTSG studies 66-01, 69-01 and 72-01 II Re-analysis of BTSG studies with EBRT 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 3.4 318 J Neurooncol (2008) 89:313–337 123
  7. 7. fractionation, hypo-fractionation and accelerated tech- niques. From the review, it would appear that hyper- fractionation has perhaps received the most interest. Hyper-fractionation Summaries of the reported randomized trials and two meta- analyses are included in the evidentiary tables. Prados et al. reported a trial of 231 patients with newly diagnosed malignant glioma randomized into two radio- therapy treatments, accelerated hyper-fractionation with a total dose of 70.4 Gy at 1.6 Gy twice daily versus con- ventional fractionation to a total dose of 59.4 Gy at 1.8 Gy daily[20]. Comparison of the two groups demonstrated similar median survivals (10.5 vs. 10.2 months, respec- tively, P = 0.75). The Phase I/II dose escalation study described by Nelson et al. randomized 435 patients using local fields and 1.2 Gy in twice daily fractions to a total doses of 64.8 Gy, 72.0 Gy, 76.8 Gy and 81.6 Gy with median survivals of 11.4, 12.8, 12.0, 11.7 months, respectively [10]. The authors were unable to demonstrate a statistically significant survival advantage between any of these groups, but noted a trend towards increased survival with 72 Gy given in twice-daily fractions. This dose is approximately biologically equivalent to the most standard conventional dose of 60 Gy. Deutsch et al. randomized 603 patients into a trial that included randomization to groups receiving conventional fractionation with either BCNU, steptozotocin or misoni- dazole or hyper-fractionated radiotherapy plus BCNU [21]. No significant difference in survival was identified. The trial by Ludgate et al. randomized 76 patients to either receive whole brain radiotherapy (40 Gy) plus local boost therapy (10 Gy) with daily treatments or hyper- fractionation to a total dose of 47.6 Gy in three times daily fractions, hence also accelerated [22]. This study is com- paratively small but also demonstrated no significant differences in survival were identified. Shin et al’s trial published in 1985 compared two frac- tionation schemes: conventional fractionation of 58 Gy in 30 once-daily fractions over 6 weeks versus 61.4 Gy in three times daily fractions [23]. An additional arm included hyper-fractionation plus midonidazole and showed no advantage. The authors found an improvement in 1-year survival comparing 41% for the hyper-fractionated group versus 20% for the conventional fractionation group with a P-value of 0.07 which the authors concluded was signifi- cant. This paper updated the paper by Fulton et al. [24] which was used in the first of the two meta-analyses noted below. An earlier trial by Shin et al. compared conventionally fractionated whole brain radiotherapy of 34 Gy in 17 fractions plus a 16 Gy local boost with hyper-fractionated (superfractionated) treatments of 40 Gy whole brain in 45 fractions plus 10 Gy local boost [25]. The authors found no significant difference between the treatment arms and noted some imbalances between the two groups. Payne et al. randomized 157 patients into two groups comparing hyper-fractionated radiotherapy to 36–40 Gy in four times daily fractions with conventional radiotherapy of 50 Gy in 25 fractions with both groups also receiving CCNU and hydrea [26]. No significant difference in med- ian survival was noted. Two meta-analyses of radiation therapy in newly diag- nosed malignant glioma were identified and reviewed. Stuschke and Thames analyzed the pooled data from the trials of Deutsch et al., Fulton et al. and Shin et al. [21] and reported a significant survival benefit for patients treated Evidentiary Table 3 Radiation volume First author/Reference Study description Data class Conclusion Kita et al./[18] Randomly assigned 49 patients to receive 40 Gy in 20 fractions to whole brain followed by a boost of 18 Gy in nine fractions; or 56 Gy in 28 fractions via local fields II Survival rates for whole brain group versus local field were 43% versus 39% at 2 years and 17% vs. 27% at 4 years (respectively). No statistical analysis reported Despite the randomized design the study is limited in size and the details of the randomization are not clear Shapiro et al./[17] Randomized trial of 571 patients with malignant glioma evaluating three chemotherapy regimens BTCG Trial 8001 In the early portion of the study all patients received 60.2 Gy whole brain radiotherapy. In 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. II No statistically significant differences in survival based on altering the radiation volume Class II because it was not clear that comparing the radiation treatment volume was the initial intent of the study J Neurooncol (2008) 89:313–337 319 123
  8. 8. with hyper-fractionated therapy with an odds ratio of 0.67 (95% confidence interval 0.48–0.93, P = 0.02). This report did not include the study by Ludgate et al. or, the updated report on the Fulton trial published as Shin et al. in 1985 and it excluded the report by Payne et al. A subsequent meta-analysis by Laperiere et al. pooled data from the studies by Payne 1982, Shin 1983 Shin 1985 and Deutsch 1989 [7]. The data from Fulton et al. included in the Stuschke and Thames review was included in the updated report by Shin et al. With the inclusion of these additional larger studies, the authors concluded that no significant survival benefit for hyper-fractionated radio- therapy could be identified when compared with conventionally fractionated radiotherapy (RR, 0.89; 95% CI, 0.73–1.09; P = 0.27). The analysis indicated no sta- tistically significant heterogeneity (v2 = 6.27, P = 0.10). The trial by Ludgate et al. was not included because the survival curves were not available for the total study group (see Evidentiary Table 4 for further details on hyper-frac- tionation) [27]. Hypo-fractionation There have been a series of single-arm prospective non- randomized trials using hypo-fractionation in a variety of regimens, generally in patients felt to have poor prognostic factors (older age and poorer performance scores). These regimens have generally been attempted to demonstrate equivalent palliative results to conventional fractionation but shorten the overall treatment time, which could have an impact on the quality of life in individuals with a short life expectancy. Several of the papers conclude that caution should be used in utilizing these regimens in patients with a better prognosis because long term cognitive follow-up was not available [28] and elderly patients who have main- tained a KPS greater than 50 may benefit from the standard conventional fractionated therapies [29]. Sultanem et al. reported a prospective non-randomized study of 25 patients with glioblastoma treated with a hypo- fractionated regimen of 60 Gy in 20 daily fractions of 3 Gy given over 4 weeks [30]. The median survival was 9.5 months. The authors concluded that although no sur- vival advantage seemed to result, the 2 week shorter treatment time appeared safe and feasible and could be advantageous in selected situations. Roa et al. randomized 100 older patients with newly diagnosed glioblastoma to either conventional fractionation of 60 Gy in 30 fractions over 6 weeks or hypo-fraction- ation of 40 Gy in 15 fractions over 3 weeks [31]. The median survivals were 5.1 versus 5.6 months, respectively, and were not significantly different (P = 0.57). The authors concluded that in the population over age 60, this hypo-fractionated regimen could be considered. Phillips et al. randomized 68 older patients (84% over 40 years of age, median age 58–59 years) with newly diagnosed glioblastoma to either conventional fractionated therapy of 60 Gy in 30 fractions over 6 weeks or to 35 Gy in 10 fractions of whole brain radiotherapy [19]. The study was closed prematurely due to poor accrual and was unable to demonstrate a significant difference, although the med- ian survival for the conventional group was longer, comparing 10.3 months for conventional fractionation versus 8.7 months for the 35 Gy group (P = 0.37). Hulshof et al. described a prospective non-randomized study examining aggressive hypo-fractionation in a group of 155 patients with glioblastoma [32]. The schemes included 33 fractions of 2 Gy, 8 fractions of 5 Gy and four fractions of 7 Gy. The authors found that the period of neurological stabilization was similar between the groups receiving four fractions of 7 Gy versus the con- ventional 33 fractions of 2 Gy and concluded that an aggressive hypo-fractionation scheme in patients with poor prognostic indicators was well tolerated and had similar survival results compared with conventional fractionation. Kleinberg et al. retrospectively reviewed 219 patients with malignant glioma treated with 51 Gy given as 30 Gy in 10 fractions to either large local fields or whole brain, followed 2 weeks later with 21 Gy in seven fractions to local fields and stratified the outcomes by RTOG recursive partitioning analysis groups [28]. The authors concluded that for RTOG groups 4–6 the hypo-fractionated regimen gave similar survival results when compared to previous RTOG trials for malignant glioma treated with conven- tional fractionation. Ford et al. performed a matched-pair analysis compar- ing 27 poor prognosis patients treated with 36 Gy in 12 fractions to 27 matched patients treated with 60 Gy in 30 fractions [33]. Comparison of the groups indicated no difference in outcome (Hazard ratio of 1.0, 95% CI 0.57– 1.74) and the authors concluded that for poor prognosis patients the shorter hypo-fractionated regimen was at least no worse than conventional fractionation. Hoegler et al. published a prospective non-randomized study of 25 patients with a median age of 73 treated with 37.5 Gy in 15 fractions [34]. Median survival was 8.0 months overall and 10.4 months in the group with KPS [ 70. The authors concluded for this group that sur- vival was similar to that achieved with conventional radiotherapy regimens and that a Phase III trial was warranted. Slotman et al. treated a group of 30 patients with GBM in a non-randomized prospective trial with 42 Gy in 14 fractions using local fields [35]. The regimen had accept- able toxicity and was well tolerated. Factors indicative of improved survival included age under 50, KPS of 80% to 320 J Neurooncol (2008) 89:313–337 123
  9. 9. Evidentiary Table 4 Hyper-fractionation First author/ Reference Study description Data class Conclusion Laperriere et al./[7] Systematic review of previous randomized studies involving hyper-fractionated radiotherapy for malignant glioma Studies included: Payne 1982 Shin 1983 Shin 1985 Deutsch 1989 Not including Scott 1998 (Abstract Only–1 year survival and number per group not reported), Ludgate1988 (no overall survival reported) I Meta-analysis Pooled analysis included four randomized studies. Two were identified but excluded as data reporting not consistent No significant survival benefit for hyper- fractionated radiotherapy was identified when compared with conventional radiotherapy (RR, 0.89; 95% CI, 0.73–1.09; P = 0.27) No statistically significant heterogeneity (v2 = 6.27, P = 0.10). Prados et al./[20] Randomized controlled trial of 231 patients with newly diagnosed GBM in four groups comparing accelerated hyperfractionated radiotherapy (70.4 Gy using two fractions per day) versus standard fractionated irradiation (59.4 Gy using daily fractions) with or without DFMO as a radiosensitizer Groups balanced with respect to age, KPS, extent of resection I No difference in groups with or without DMFO Accelerated Hyper-fractionated (2 arms): Overall Survival 10.5 months, Standard Radiation Therapy (2 arms): Overall Survival 10.25 months (P = 0.75) The authors concluded that there was no survival benefit observed with accelerated hyper- fractionated therapy Stuschke M et al., Int J Radiat Oncol Biol Phys 1997 [27] Meta-analysis including three previously reported randomized trials including hyper-fractionation in newly diagnosed malignant glioma Studies included: Deutsch 1989 Fulton 1984 Shin 1983 II Meta-analysis The authors reported a trend in favor of hyper- fractionation with O.R. of 0.67 (95% CI 0.48– 0.93, P = 0.02). Small number of studies limits interpretation Nelson et al./[10] Randomized controlled trial of 435 analyzed patients with newly diagnosed malignant glioma initially into three arms receiving 1.2 Gy fractions twice daily; 64.8 Gy 72.0 Gy 76.8 Gy, and subsequently into two arms: 72.0 Gy 81.6 Gy All patients also received BCNU Local field radiotherapy used and defined as edema on imaging plus 2.5 cm margin II Complicated study to interpret due to the change in the radiation doses used over the sequence Median survival: 64.8 Gy 11.4 months 72.0 Gy 12.8 months 76.8 Gy 12.0 months 81.6 Gy 11.7 months The authors report no significant differences between any of the groups but note the trend towards increased survival at the 72.0 Gy dose 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) J Neurooncol (2008) 89:313–337 321 123
  10. 10. Evidentiary Table 4 continued First author/ Reference Study description Data class Conclusion Deutsch et al./[21] Randomized controlled trial of 603 patients with newly diagnosed malignant glioma in four groups: Standard radiotherapy plus BCNU Standard radiotherapy (60 Gy in 30–35 fractions) plus streptozotocin Hyper-fractionated radiotherapy (66 Gy in 60 fractions–twice daily) plus BCNU Standard radiotherapy plus misonidazole and BCNU I Median survivals: Standard radiotherapy plus BCNU 9.9 months Standard radiotherapy plus streptozotocin 9.9 months Hyper-fractionated radiotherapy plus BCNU 10.4 months Standard radiotherapy plus misonidazole and BCNU 9.2 months No statistically significant difference between any of the groups and no advantage to hyper- fractionation Ludgate et al./[22] Randomized controlled trial of 76 patients with newly diagnosed GBM comparing whole brain radiotherapy plus 10 Gy local boost delivered daily treatments to 40 Gy versus three fractions per day to a dose of 47.6 Gy I Median survival: Daily fraction group 8 months Hyper-fractionated group 11.5 months (P-value reported as not significant) 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 reasons Shin et al./[23] Randomized controlled trial in newly diagnosed malignant astrocytoma comparing two fractionation schemes with misonidazole (124 patients): Conventional fractionation (58 Gy in 30 fractions over 6 weeks) 38 patients versus Multiple daily fractions (61.4 Gy three daily fractions over 4.5 weeks) 43 patients versus Multiple daily fractions plus midonidazole 43 patients I One year survival rate: Coventional fractionation 20% Multiple daily fractionation 41% Multiple daily plus midonidazole 45% No significant difference between fractionation schemes favoring multiple daily fractions (P = 0.07). No effect of midonidazole Shin et al./[25] Randomized controlled trial for newly diagnosed malignant astrocytoma comparing: Superfractionated radiotherapy (40 Gy in 45 fractions whole brain with 10 local boost) 34 patients versus conventional fractionated radiotherapy (34 Gy in 17 fractions whole brain with 16 Gy local boost) 35 patients I One year survival: Conventional fractionated therapy 10% Superfractionated therapy 32% Two year survival: Conventional fractionated therapy 21% Superfractionated therapy 54% Median survival: 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) 322 J Neurooncol (2008) 89:313–337 123
  11. 11. 100% and 75% or greater resection. If none of those factors were present the median survival dropped to 6.25 months. Bauman et al. treated 29 patients with GBM with poor prognostic factors (age greater than 64 and KPS less than 50) with 30 Gy whole brain radiotherapy in 10 fractions over 2 weeks [29]. They compared their median survival of 6 months with historical controls of 35 similar patients treated with 50 Gy (median survival of 10.1 months) and 28 patients receiving supportive care only (median survival of 1 month). The authors concluded that the hypo-frac- tionated course could be used in elderly patients with poor prognosis and that conventional therapy should be con- sidered in the elderly patient with a higher KPS. Thomas et al. used a scheme of 30 Gy in six fractions using local fields over 2 weeks in 38 patients with malig- nant glioma and poor prognostic indicators and found a median survival of 6 months [36]. They felt the regimen was well tolerated and provided effective palliation but indicated definitive conclusions would require randomized data. Glinski et al. published a randomized controlled trial of 108 patients including 44 with glioblastoma and 64 with anaplastic astrocytoma with two arms: conventional frac- tionation (50 Gy whole brain plus 10 Gy in five fractions to the tumor) or hypo-fractionation (two courses of 20 Gy in five fractions separated by a month and followed a month later by 10 Gy in 5 as a boost to the tumor) [37]. The groups appeared to be well balanced. Reporting on the 2- year survival there was no survival advantage for the anaplastic astrocytoma groups (22% vs. 18%, P [ 0.05), However, they found a survival advantage in the subgroup of 44 glioblastoma patients treated with hypo-fractionated split regimen of 23% versus 10% (P 0.05). See Evidentiary Table 5 for further particulars on hypo- fractionation. Accelerated radiotherapy Brada et al. described a single arm non-randomized study described the treatment of 211 patients with malignant glioma treated with 55 Gy in 34 twice daily fractions [38]. The median survival was 10 months. In comparing to a historical control group treated with 60 Gy in 30 fractions the authors concluded their results were nearly identical. They added the opinion that given the lack of clear survival advantage, the logistics of administering multiple fractions per day appeared to be an unnecessary complication. Werner-Wasik et al. published their randomized con- trolled trial evaluating dose escalation, hyper-fractionation and accelerated dosing in 747 evaluable patients (RTOG 83-02) [39]. The accelerated group received 1.6 Gy twice daily to doses up to 54 Gy. Although they found low toxicity with the accelerated regimen, the median survival of 10. 2 months for glioblastoma and 40.3 months for anaplastic astrocytoma was not significantly different than the hyper-fractionated regimen or from historical conven- tionally fractionated controls (10.2 vs. 10.8 months, P = 0.08 for glioblastoma and 42.3 versus 40.3 months, P = 0.67 for anaplastic astrocytoma). Horiot et al. reported on the results of an EORTC ran- domized controlled trial of 340 malignant glioma patients [40]. The study involved three arms: 60 Gy in 30 fractions over 6 weeks (conventional fractionation), 60 Gy total but given in 2 Gy fractions three times daily for 1 week (30 Gy) and then repeated after 2 week interval (acceler- ated fractionation). The third group consisted of the Evidentiary Table 4 continued First author/ Reference Study description Data class Conclusion Payne et al./[26] Randomized controlled trial comparing 157 patients with newly diagnosed malignant astrocytoma treated with Hyper-fractionated (36–40 Gy given four fractions per day) versus Standard radiotherapy (50 Gy in 25 fractions) Both groups received CCNU and hydrea I Median survival: Hyper-fractionated 10.6 months Standard radiotherapy 10.2 months (P = NS) No significant survival or toxicity differences were seen between the two groups Scott et al. Proceedings of the Annual Meeting of ASCO 1998 Randomized comparison of hyper- fractionated rad iotherapy to 72.0 Gy versus standard radiotherapy RTOG 9006 712 patients with malignant glioma Patients also received BCNU Not Graded Presented as an abstract only. It is included here for reference because it is a large trial that is referred to in the literature with some frequency Authors reported no significant difference in median survival between the two groups Limited data available precluded this large negative study from being included in subsequent meta-analysis J Neurooncol (2008) 89:313–337 323 123
  12. 12. accelerated fractionated regimen plus misonidazole. Although the detail provided in this paper is minimal, the authors reported no significant difference between any of the groups (P-value not reported). They did not describe an increase in toxicity with the accelerated regimen. Keim et al. described a non-randomized comparison of 38 patients with GBM treated with an accelerated radio- therapy regimen of 1.6 Gy three times daily to a total dose of 60 Gy [41]. They found a median survival of 10.5 months. Comparison to similar group of 26 patients treated with conventional fractionation found no significant difference (P-value not reported). The authors concluded that there were no increased problems with the accelerated regimen but it did not improve survival. Simpson and Platts published a randomized trial of 134 patients with glioblastoma initially with three treatment Evidentiary Table 5 Hypo-fractionation First author/ Reference Study description Data class Conclusion Sultanem et al./[30] Prospective trial of 25 patients with GBM treated with a hypo-fractionated radiotherapy. 60 Gy in 20 daily fractions of 3 Gy to the tumor volume, and 40 Gy in 20 fractions of 2 Gy over 4 weeks III Median survival 9.5 months (range: 2.8–22.9 months) One-year survival rate 40% Median progression-free survival was 5.2 months (range: 1.9–12.8 months) The 2-week reduction in the treatment time may be a valuable benefit for this group of patients. However, despite this accelerated regimen, no survival advantage has been observed Roa et al./[31] Randomized controlled trial of 100 patients with newly diagnosed GBM over age 60. Two groups: 60 Gy in 30 fractions over 6 weeks versus 40 Gy in 15 fractions over 3 weeks I Median survival: 60 Gy group 5.1 month 40 Gy group 5.6 month P = 0.57 6 month survival: 60 Gy group 44.7% 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 60 Phillips et al./[19] Randomized controlled trial in newly diagnosed GBM (closed early for slow accrual) 84% of all patients were over 40 years of age. Two groups: 60 Gy in 30 fractions over 6 weeks–Local field (n = 36) versus 35 Gy in 10 fractions–Whole Brain Radiotherapy (n = 32) I Median survival: 60 Gy group 10.3 month 35 Gy group 8.7 month P = 0.37 Risk of dying over course of the study appeared increased in the whole brain radiotherapy with RR of 1.47 (95% CI 0.89–2.42) but was not significant Hulshof et al./[32] Prospective non-randomized comparison of conventional and hypo-fractionated radiotherapy in GBM 155 patients Three different radiation schemes were used; 33 9 2 Gy 8 9 5 Gy 4 9 7 Gy III Median survival: 33 9 2 Gy 7 months 8 9 5 Gy 5.6 months 4 9 7 Gy 6.6 months In general, patients in the hypo-fractionation group had far worse prognostic factors compared with patients treated with the conventional scheme 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 fractionation 324 J Neurooncol (2008) 89:313–337 123
  13. 13. Evidentiary Table 5 continued First author/ Reference Study description Data class Conclusion Kleinberg et al./[28] Retrospective review and classification of 219 patients with malignant glioma treated with 51 Gy delivered as 30 Gy in 10 fractions to large field or whole brain, followed 2 weeks later with 21 Gy in seven fractions Outcomes stratified by RTOG RPA classes III The six RTOG prognostic groupings were significantly predictive of outcome for patients treated with this shortened regimen (log rank P 0.001) Median survival (months) Two-Year Survival (%) RTOG Class 1 68 64 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 scheme Ford et al./[33] Matched case–control 32 poor prognosis patients with GBM treated with 36 Gy in 12 fractions Compared with matched patients receiving 60 Gy in 30 fractions II 27 pairs were used Median survival for the 36 Gy group was 4 months Comparison with control group resulted in a Hazard ratio of 1.0 (95% CI was 0.57–1.74) For poor prognosis patients the shorter regimen was no worse than the standard Hoegler et al./[34] Prospective non-randomized study of 25 patients with GBM treated with 37.5 Gy in 15 fractions. Median age 73 years III Median survival (overall group) 8.0 months Median survival (if KPS [ 70) 10.4 months The authors conclude that for this elderly group the survival was similar to longer radiotherapy regimens and that a Phase III study was warranted Slotman et al./[35] Prospective non-randomized study of 30 patients with GBM treated with 42 Gy in 14 fractions to the tumor plus 3 cm III Median survival was 9 months for the overall group Three prognostic factors were identified 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 months Bauman et al./[29] Prospective single arm trial. 29 patients with GBM poor prognosis (age greater than 64 years or KPS less than 50) treated with 30 Gy whole brain in 10 fractions over 2 weeks III Median survival 6 months Compared with historical cohorts, 35 similar patients treated with greater than 50 Gy (Median survival 10.1 months) and 28 patients treated with supportive 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 J Neurooncol (2008) 89:313–337 325 123
  14. 14. arms [42]. These included whole brain radiotherapy to 30 Gy given either as three times daily over 1 week, three times daily over 3 weeks or daily for 3 weeks. As the study progressed (presumably based on the safety evaluation and lack of efficacy) the doses were adjusted upwards to include 40 Gy. The authors found no difference in survival between any of the groups in this study (see Evidentiary Table 6 for further points on accelerated radiotherapy). Brachytherapy Brachytherapy is a technique that utilizes the placement of radioactive seeds in and around tumors to increase, or boost, the delivery of local radiation. Both temporary and permanent sources have been described and a variety of radioactive sources have been utilized, with the majority of more recent studies in malignant glioma describing the use of I-(125). Theoretically this could offer an advantage in malignant glioma when the tumors are unifocal at presen- tation and because the majority of tumors progress or recur within 2 cm of their original location. Two randomized studies, one matched control study and a series of retro- spective studies of interest are abstracted in the Evidentiary Table 7. Significant effort has gone into attempting to identify patients with malignant glioma who would benefit from this technique. Generally patients selected for brachyther- apy have good KPS and smaller, more focal tumors. Wen et al. described a series of matched control patients with a median survival in the implant group of 18 months versus 11 months in the control group (P 0.0007) [43]. Similar encouraging results in non-randomized fashion were observed by Sneed et al. in two separate reports (median survivals of 19 months) and Chang et al. (median survival 19.5 months with brachytherapy vs. 12.5 months without) [44–46]. Effect of dose rate delivered by different isotopes was studied by Koot et al. and did not appear to alter the survival [47]. A number of investigators have applied the RTOG recursive partitioning analysis to brachytherapy series. Videtic et al. evaluated the effect of tumor volume on survival, finding that the observed inverse relationship between tumor volume implanted and survival disappeared within each RPA class suggesting that even patients with larger volumes may benefit from brachytherapy [48]. Chang et al. evaluated a series of 28 patients stratified by RPA class finding an overall trend in favor of brachy- therapy but due to the small numbers in each class only found significance in RPA class 5 [46]. Lamborn et al. evaluated 832 patients involved in eight different clinical trials finding that in addition to extent of resection, che- motherapy, age and KPS brachytherapy also had a significant effect on survival [49]. Despite these thoughtful and promising results, there have been two randomized trials of brachytherapy that failed to demonstrate a survival advantage for brachyther- apy when added to the treatment regimen for newly diagnosed malignant glioma. Laperriere et al’s study pub- lished in 1998 randomly assigned 140 patients to external Evidentiary Table 5 continued First author/ Reference Study description Data class Conclusion Thomas et al./[36] Prospective non-randomized study of 38 patients with malignant glioma and poor prognosis treated with 30 Gy in six fractions over 2 weeks to the enhancement plus 2 cm III Median survival 6 months One year survival rate 23% The authors conclude that this hypo-fractionated regimen was well tolerated, convenient and provided effective palliation. They indicated that comparison with conventional radiotherapy or supportive care only would require randomized studies Glinski/[37] Randomized controlled trial of 108 patients with malignant glioma (44 GBM, 64 AA). Randomized to two arms: Conventional fractionation (50 Gy Whole brain plus 10 Gy in 5 fraction local boost to the tumor) and Hypo-fractionated (three courses separated by one month interval 20 Gy in 5 times two plus 10 Gy in 5 fraction boost) II An analysis of all 108 randomized patients demonstrated no significant difference in survival between the treatment arms Non-significant difference in the 64 patients with AA (22% vs. 18%, P [ 0.05) Significant survival benefit favoring hypo-fractionated radiation compared with conventional radiation in the subgroup of 44 patients with glioblastoma (23% vs. 10% at 2 years; P 0.05) Long-term neuropsychological data is lacking in these groups. The mixed groups limits the numbers and limits interpretation 326 J Neurooncol (2008) 89:313–337 123
  15. 15. radiotherapy of 50 Gy in 25 fractions over 5 weeks (69 patients) versus the same external radiotherapy plus tem- porary stereotactic iodine-125 implants with a minimum peripheral tumor dose of 60 Gy (71 patients) [50]. Median survival for the brachytherapy arm was 13.8 months versus 13.2 months for the non-brachytherapy arm (P = 0.49). Improved survival was associated with either chemother- apy or reoperation at progression (P = 0.004) or KPS greater than or equal to 90 (P = 0.007). The authors concluded that stereotactic radiation implants did not demonstrate a statistically significant improvement in sur- vival in the initial management of patients with malignant glioma. Although the initial report of the Brain Tumor Coop- erative Group (BTCG Trial 87-01) randomized trial of radiotherapy plus BCNU with and without interstitial radiation for a total dose of 60 Gy at the tumor periphery suggested a significant survival advantage, the subsequent Evidentiary Table 6 Accelerated radiotherapy First author/ Reference Study description Data class Conclusion Brada et al./[38] Single arm study of 211 patients with malignant glioma treated with 55 Gy in 34 fractions (twice daily). Compared to historical control of similar group treated with 60 Gy in 30 fractions over 6 weeks III Median survival 10 months, The authors state that their results are similar to a matched cohort of patients who had received 60 Gy in 30 fractions over 6 weeks in a previous MRC study and felt that a matched comparison would yield similar results Overall conclusion was that accelerated treatments complicated the logistics for delivery of radiotherapy and added nothing to survival Werner-Wasik et al./ [39] Randomized controlled dose escalation study randomized to hyper-fractionated (1.2 Gy twice daily to 64.8, 72, 76.8, 81.8 Gy) or accelerated radiotherapy (1.6 Gy twice daily to doses of 48 or 54.4 Gy) RTOG 83-02 786 patients (747 eligible and evaluable) 81% GBM and 19% AA) All patients recieved BCNU I Overall median survival for GBM: Hyper-fractionated 10.8 months Accelerated hyper-fractionated 10.2 months P = 0.08 Overall median survival for AA Hyper-fractionated 42.3 months Accelerated hyper-fractionated 40.3 months P = 0.67 Overall analysis indicated no significant survival difference among any of the dose schemes (P = 0.598). There was low toxicity with accelerated fractionation Horiot et al./[40] Randomized controlled trial (EORTC Protocol 22803. 340 patients with malignant glioma into three arms. 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) II Minimal details reported but the authors concluded that there was no difference in survival between the three treatment groups (P-value not reported). No increased toxicity with accelerated radiation Keim et al./[41] Non-randomized comparison of 38 patients with GBM treated with accelerated radiotherapy (1.6 Gy three times daily to total dose of 60 Gy) compared to 26 patients treated with 60 Gy in 30 fractions over 6 weeks III Median survival 10. 5 months. No difference between these two treatment groups. P-value not reported The authors concluded that the tolerance of the accelerated schedule was as good as the conventional but that survival was not improved Simpson and Platts/ [42] Randomized trial of 134 patients with GBM with three treatment groups Total whole brain dose of 30 Gy (in initial group three times daily for 1 week, three times daily for 3 weeks or daily for 3 weeks) Doses were escalated to 40 Gy in later portions of the study) II No significant difference noted between any of the groups. All P-values greater than 0.05 Although reported as a randomized study, the detail included makes evaluation difficult J Neurooncol (2008) 89:313–337 327 123
  16. 16. published report did not. The final report of Selker et al. described this randomized multi-center comparison of surgery, EBRT and BCNU (n = 137) versus surgery, EBRT, BCNU and I-125 brachytherapy boost (n = 133) in newly diagnosed malignant glioma (299 total patients, with 270 (90%) in the valid study group) [51]. The median survival, with all pathologies included, for surgery, EBRT and BCNU (control) was 14.7 months compared to 17.0 months for surgery, EBRT, BCNU and (125)-I brachytherapy (P = 0.101). In the GBM only group (n = 230) the median survival was 14.5 for control (n = 107) and 16.0 months for the brachytherapy group (n = 123), (P = 0.169). As in most previous studies, age, KPS, and pathology were all independent predictors of mortality. Incorporating an adjustment for these variables in both stratified and Cox proportional hazard models failed to demonstrate any statistically significant differ- ences in survival between these two treatment groups. The authors concluded that no long-term survival advantage was demonstrated with the addition of (125)-I brachy- therapy to surgery, EBRT and BCNU in patients with newly diagnosed malignant glioma (see Evidentiary Table 7 for further details on brachytherapy) [52, 53]. Stereotactic radiosurgery Stereotactic radiosurgery is used to provide a single fraction of radiation utilizing computer assisted stereo- tactic technique. A series of encouraging reports initially described the use of radiosurgery as a focal radiation dose boost in conjunction with fractionated external beam radiotherapy. Selected studies are detailed in the Evidentiary Table 8 (Stereotactic Radiosurgery). These studies represented early trials in determining the safety and feasibility of this technique and generally compared study outcome to historical controls from the RTOG RPA data. Reported median survivals for GBM ranged from 10 to 20 months and 2-year survivals ranged from 20% to 40%. Reoperation following these combined radiotherapy technique ranged from 10 to 30%. Essen- tially all of these authors acknowledged the limitations of their studies and given the limited toxicity observed, indicated the need for a randomized prospective study to evaluate the role of SRS in newly diagnosed malignant glioma. The question of selection bias is of concern as noted for brachytherapy trials and has been addressed. Initially, Curran et al. applied previously used selection criteria for SRS (KPS [ 60, tumor diameter of 4.0 cm or less, and superficial location) to patients entered in a separate trial not involving SRS [54]. They found that the median sur- vival for SRS eligible patients was 14.4 months versus 11.7 months for SRS ineligible patients (P = 0.047) suggesting that there appeared to be a survival advantage favoring patients eligible for stereotactic radiosurgery, primarily based on the inclusion of a subgroup with a higher KPS. Subsequently, Lustig et al. applied the entry criteria for the RTOG 93-05 randomized trial of EBRT plus SRS versus EBRT alone, to a previous randomized RTOG trial not involving SRS using RTOG RPA analysis [55]. They reported that no significant difference could be demonstrated between the two groups comparing the SRS eligible versus the SRS ineligible groups, supporting the outcome of the trial subsequently reported by Souhmai et al. [56]. These reports highlight the importance of careful interpretation of individual studies and the need to avoid extrapolation of the results to patient groups not specifically studied in a given trial. The results of the RTOG 93-05 trial were reported by Souhami et al. and are outlined in the evidentiary table for stereotactic radiosurgery [56]. This prospective multi-cen- ter randomized trial recruited 203 patients. Seventeen patients were excluded from final analysis including seven who were randomized to SRS but had tumor treatment diameters greater than 40 mm at the time of SRS. Ten additional patients were excluded based on histology (n = 3), refusal or withdrawal (n = 4), multifocal tumor (n = 1), prior chemotherapy (n = 1) and failure to record KPS (n = 1), leaving 186 patients for evaluation. Ninety- seven were randomized to EBRT alone and eighty-nine to EBRT plus SRS. Both groups received IV BCNU. Median survival was 13.6 in the EBRT group and 13.5 in EBRT plus SRS (P = 0.57) with no significant difference in two and three survival rates or quality of life measures. The authors conclude that stereotactic radiosurgery followed by EBRT and BCNU does not improve outcome in patients with newly diagnosed GBM. Despite a relatively large number of preliminary trials suggesting a survival benefit, currently randomized data does not support the use of stereotactic radiosurgery as a routine addition to the initial management of glioblastoma. Selected patients may benefit but the specific characteris- tics of this group have yet to be identified (see Evidentiary Table 8 for further particulars on stereotactic radiosurgery) [57–66]. Summary and key issues for future investigation Review of the literature published to date provides clear and consistent class I data supporting the role of adjuvant radiation therapy in the treatment of glioblastoma. Early studies provide evidence comparing radiation therapy to supportive care, chemotherapy and combinations of ther- apy and virtually all conclude that arms that included radiation therapy had enhanced survival. 328 J Neurooncol (2008) 89:313–337 123
  17. 17. Data supporting the most common conventional dose of approximately 60 Gy in 30 fractions of 2 Gy each are ubiquitous. Studies looking at lower doses in conventional fashion and higher doses in conventional fashion appeared either inferior or of no additional benefit. Several attempts to utilize altered fractionation schemes have been studied. Hyper-fractionated radiotherapy, with- out significant acceleration in terms of delivery duration, has been explored in class I studies and failed to show a significant benefit. A roughly equivalent biological dose to Evidentiary Table 7 Brachytherapy First author/ Reference Study description Data class Conclusion Lamborn et al./ [49] Survival analysis of single institution data accumulated from eight clinical prospective trials on 832 newly diagnosed GBM (based on 776 with complete data) Analysis using Cox proportional hazards modeling and recursive partitioning analyses II Multivariate analysis (Cox) indicated significant effect of: Chemotherapy Hazard Ratio 0.60 P 0.001 Extent of resection Hazard Ratio 0.75 P 0.001 KPS Hazard Ratio 0.97 P 0.001 Age Hazard Ratio 1.03 P 0.001 Brachytherapy Hazard Ratio 0.60 P 0.001 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 data Chang CN et al., J Neurooncol 2003 [52] Comparative study of 28 newly diagnosed GBM treated postop with EBRT and brachytherapy (high dose rate HDR) and 28 controls treated without the addition of brachytherapy Selection based on patient or physician preference All deemed eligible for brachytherapy: Unilateral, supratentorial, less than 6 cm, KPS over 60 without subependymal spread III Median survival: EBRT plus brachytherapy 19.5 months EBRT 12.5 months (P-value not stated) Two year survival: EBRT plus brachytherapy 61% EBRT 28% (P = 0.12) Median survival by RTOG RPA Class: Class 3: 41.6 versus 21.2 months (P = 0.39) Class 4: 16.7 versus 12.1 months (P = 0.37) 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 proposed Mayr, M. et al. Int J Oncol 2002 [53] Retrospective review of 73 patients (67 evaluable) treated with brachytherapy Includes 17 newly diagnosed GBM and 28 recurrent III Median survival for newly diagnosed GBM was 9.02 months For patients with a glioblastoma multiforme, median 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 J Neurooncol (2008) 89:313–337 329 123
  18. 18. the conventional fractionated dose of 60 Gy (72 Gy in 60 fractions) appeared the best choice in large hyper-frac- tionated series that looked at both higher and lower doses [10]. The additional effort in delivering twice or three times daily treatment is generally felt to increase the difficulty of treatment and hence without a clear benefit in survival is not recommended. Hypo-fractionated radiotherapy has been studied in several class I level studies in selected older or more poorly performing patients and has appeared to do as well as conventional fractionation [19, 31]. Despite this a Evidentiary Table 7 continued First author/ Reference Study description Data class Conclusion Selker et al./[51] Randomized multicenter comparison. Newly diagnosed malignant glioma (299 patients, 270 (90%) in valid study group). Surgery, EBRT and BCNU (n = 137) versus Surgery, EBRT, BCNU and (125)-I brachytherapy boost (n = 133) I Brain Tumor Cooperative Group NIH Trial 87-01 trial to investigate the effect of implanted radiation therapy in addition to surgery, EBRT and BCNU in newly diagnosed GBM Median survival (all pathologies included): Surgery, EBRT, BCNU (control) 14.7 months 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 glioma Koot et al./[47] Comparative study of two methods of brachytherapy applied to 84 patients with newly diagnosed GBM treated in two different centers. All treated with EBRT. Biopsy plus I-(125) implant (n = 45) and Resection plus Ir-(192) implant compared with Surgery plus EBRT (n = 18) III Median survival (for Age [ 50, KPS [ or = 70, non- midline): I-(125) group 17 months Ir-(192) group 16 months Control 10 months (no p value reported) Volume: 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 group 330 J Neurooncol (2008) 89:313–337 123
  19. 19. large and inclusive trial with a hypo-fractionated arm has not been performed. Concerns regarding long term sequelae with very limited fractionation schemes has lead to poor accrual and concerns for a more inclusive population [19, 28]. Accelerated fractionation has also failed to show a significant benefit in class I studies [39, 40]. Evidentiary Table 7 continued First author/ Reference Study description Data class Conclusion Videtic et al./[48] Single center stratification of GBM patients treated with surgery, EBRT and I-(125) brachytherapy at initial diagnosis by RPA survival class focusing on the relationship between implant volume and survival and whether volume acted as a prognostic variable within each RPA class Review of 52 (of 53) GBM patients Class III–12, Class IV–26 Class V–13 Class VI–1. Mean age 57.5 years (range 14–79). Median KPS 90 (range 50–100) Median follow-up 11 months III Two-year survivals and median survival for implanted GBM patients compared to the RTOG database: Class III 74% versus 35% and 28 months versus 17.9 months Class IV 32% versus 15% and 16 months versus 11.1 months Class V/VI 29% versus 6% and 11 months versus 8.9 months Mean implanted tumor volume was 15.5 cc (range 0.8–78) Plotting survival as a function of 5-cc TV increments suggested a trend toward poorer survival as the implanted volume increases Effect of implanted volume on survival by RPA class: Class III no significant difference observed 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 implantation Laperriere et al./[50] Randomized prospective trial of 140 patients with newly diagnosed GBM Two Groups: EBRT 50 Gy in 25 fractions (n = 69) EBRT 50 Gy in 25 plus I 125 brachytherapy to 60 Gy (n = 71) I Median survival: EBRT 13.2 months EBRT plus brachytherapy 13.8 months (P = 0.49) Improved survival associated with either chemotherapy or reoperation at progression (P = 0.004) or KPS greater 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 GBM Sneed et al./[44] Randomized single-institution study of hyper-thermia in addition to surgery, EBRT, brachytherapy in newly- diagnosed GBM 35 patients treated with hyper-thermia versus 33 without III for brachytherapy data Evaluation of effect of adjuvant interstitial hyper-thermia (HT) in patients with glioblastoma undergoing brachytherapy boost after conventional radiotherapy Median survival: Surgery, EBRT and brachytherapy 19.0 months 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 brachytherapy J Neurooncol (2008) 89:313–337 331 123
  20. 20. The treatment volume for external beam radiotherapy is perhaps the most incompletely studied question despite clear patterns of care being established. Most studies sup- porting the role of adjuvant radiation therapy used whole brain radiotherapy, a technique that is not recommended as a standard approach today. One class I/II study compared a whole brain dose of 40 Gy plus a boost of 18 Gy to an approach using local fields for 56 Gy and found no dif- ference in outcome at 2 years [18]. In addition BTCG trial 8001 allowed a change during the protocol accrual to limit the whole brain dose to 43 Gy followed by a boost and found no difference compared to the traditional whole brain dose of 60 Gy [17]. This taken along with class III data showing that more than 80% of recurrences occurred within 2 cm of the resection and enhancing volume bed support the strategy of deleting whole brain radiotherapy. Despite this generally accepted practice of treating the edema volume with an approximately 2 cm margin fol- lowed by a boost to the enhancing volume with 1–2 cm margin––there is little class I data addressing the issue of appropriate volume in glioblastoma or malignant glioma. The addition of boost doses of radiation therapy and in particular both brachytherapy and stereotactic radiosurgery have been extensively studied in recent years. Large institutional class III trials suggested potential benefit for brachytherapy and lead to class I randomized trials [43– 46]. Unfortunately, class I trials did not show the promising results of the previous more selected and uniform institu- tional series and failed to show a benefit to brachytherapy [50, 51]. Similarly, several large and controlled institu- tional and non-randomized multi-institutional trials suggested the potential of benefit for stereotactic radio- surgery. Despite this promise the test of a randomized trial via the RTOG 93-05 failed to show a survival benefit for dose escalation achieved through stereotactic radiosurgery [56]. These techniques are therefore not recommended as a standard component of therapy for glioblastoma or malig- nant glioma. Evidentiary Table 7 continued First author/ Reference Study description Data class Conclusion Sneed et al./[45] Retrospective review of newly diagnosed GBM treated with EBRT and I-(125) brachytherapy (n = 159) III Retrospective review undertaken to examine the influence of age on the survival of patients undergoing 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 review of 56 newly-diagnosed glioblastoma patients Surgery, EBRT, and (125)-I brachytherapy (additional 50 Gy to the tumor bed). Compared to 40 matched controls II Median survival: Brachytherapy 18 months Control 11 months (P 0.0007) Two-year survival: Brachytherapy 34% 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 332 J Neurooncol (2008) 89:313–337 123
  21. 21. Evidentiary Table 8 Stereotactic radiosurgery First author/ Reference Study description Data class Conclusion Souhami et al./[7] Randomized prospective trial of 203 patients with newly diagnosed supratentorial GBM (tumor less than or equal to 40 mm maximum cross section after surgery) Postop SRS plus EBRT (60 Gy) plus BCNU (n = 89) versus EBRT plus BCNU (n = 97) SRS dose volume dependent (range 15 to 24 Gy) Median followup 61 months 17 patients excluded consisting of 10 for path, patient refusal or protocol violation and 7 for tumor size greater than 40 mm at time of SRS I This study investigated the effect of stereotactic radiosurgery (SRS) added to conventional external beam radiation therapy (EBRT) with carmustine (BCNU) on the survival of patients with newly diagnosed GBM Median survival: SRS plus EBRT/BCNU 13.5 months (95% CI 11.0–14.8 months) EBRT/BCNU 13.6 months (95% CI 11.2–15.2 months) P = 0.57 There were also no significant differences in 2- and 3-year survival rates and in patterns of failure between the two arms Quality of life deterioration and cognitive decline equivalent. No difference in quality-adjusted survival between the arms The authors concluded that stereotactic radiosurgery followed by EBRT and BCNU did not improve the outcome, quality of life or cognitive function in patients with newly diagnosed GBM Cho, K. H. et al. Technol Cancer Res Treat 2004 [64] Retrospective review of 24 patients with newly diagnosed GBM treated with EBRT plus a stereotactic boosted therapy Fourteen patients (58%) were treated with stereotactic radiosurgery (SRS) and 10 patients (42%) with fractionated stereotactic radiotherapy (FSRT) III This study compared single dose or fractionated stereotactic boosted therapy plus EBRT in newly diagnosed GBM Overall median survival 16 months Overall 1 year survival rate 63% Overall 2 year survival rate 34% Median survival: RTOG Class 3 28.3 months (expected 11.1) 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 warranted Lustig et al./ [55] Study applying the entry criteria of the RTOG 93-05 trial (Souhami et al 2004) to the patient enrolled in the RTOG 90-06 trial comparing 60 Gray versus 72 Gray in patients with GBM to evaluate possible selection bias of the SRS entry criteria 599 total patients. 137 Eligible and 372 Ineligible for 93-05 Radiation Therapy Oncology Group (RTOG) Recursive partitioning analysis (RPA) was used to evaluate for differences II Comparison of Median survival by RTOG RPA Class for patient either eligible or ineligible for SRS trial: Median survival SRS eligible RTOG RPA Class 3 16.8 months RTOG RPA Class 4 12.0 months RTOG RPA Class 5 8.3 months RTOG RPA Class 6 1.7 months Median survival SRS ineligible RTOG RPA Class 3 16.8 months (P = NS) RTOG RPA Class 4 10.8 months (P = 0.042) RTOG RPA Class 5 7.2 months (P = 0.09) 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 J Neurooncol (2008) 89:313–337 333 123
  22. 22. Evidentiary Table 8 continued First author/ Reference Study description Data class Conclusion Nwokedi, E. C., et al. Neurosurgery 2002 [65] Retrospective review of 82 patients with GBM. 64 included in review 33 treated with EBRT and 31 treated with EBRT plus SRS (10– 28 Gray) Miniumum followup of 1 month reported III Retrospective review of the impact of SRS on patients treated for GBM Median survival: EBRT 13 months EBRT plus SRS 25 months (P = 0.03) Predictors of overall survival by Cox regression analysis included: age, KPS and SRS 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 study Shrieve, D. C., et al. J of Neurosurg 1999 [66] Retrospective review of 78 patients treated with EBRT and SRS boost III Median survival 19.9 months One year survival 88.5% 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 trial Kondziolka, D., et al Neurosurgery 1997 [61] Retrospective review of 109 patients involving SRS in additional to EBRT in malignant glioma management Included n = 45 newly diagnosed GBM and n = 21 AA III For newly diagnosed (SRS plus EBRT): Median survival: GBM 20 months (s.d. 2.6) range 5 to 76 months, AA 56 months (s.d. 8.9) range 9 to 93 months Two year survival: GBM 41%, AA 88% Reoperation rate: GBM 19%, AA 23% The authors conclude that SRS appears promising and call for a randomized tria Larson, D. A., et al. Int J Radiat Biol Phys 1996 [62] Retrospective review of 189 patients either primary or recurrent malignant glial tumor patients treated with SRS as a portion of their overall treatment. Includes 41 newly diagnosed GBM and 16 AA Patients stratified by whether they would be eligible for brachytherapy in previous protocols III Median survival: GBM Brachytherapy eligible 21.5 months Brachytherapy ineligible 10 months (P = 0.01) AA Brachytherapy eligible 24 months Brachytherapy ineligible 24 months (P = NS) Tumor grade, age, KPS, smaller volume, unifocal tumor all correlated with prolonged survival The authors conclude that bias in patient selection is concerning and support need for randomized trial Sarkaria, J. N., et al. Int J Radiat Biol Phys 1995 [63] Combined retrospective analysis of data from three centers (Masciopinto et al., Buatti et al., Shrieve et al.) 115 patients with newly diagnosed malignant glioma (96 GBM and 19 AA) III Stratified by and Compared to RTOG RPA analysis: SRS boost RTOG RPA Class 3 38.1 months RTOG RPA Class 4 19.6 months RTOG RPA Class 5/6 13.1 months 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 trial 334 J Neurooncol (2008) 89:313–337 123
  23. 23. Review of this data leads to the conclusion that radiation therapy should be recommended as standard therapy for glioblastoma and malignant glioma as supported by con- sistent class I data. Patients with good prognosis can confidently be treated with conventional doses of 60 Gy in 30 fractions as supported by the body of the literature. Consideration for hypo-fractionated regimens especially in the setting of poor prognosis is very reasonable and is supported by the literature in class I data. Other altered fractionation schemes are not supported outside a study setting. Local fields are generally used to treat the tumor volume as identified on imaging with a 1–2 cm margin. Although there is minimal Class I support for this, the preponderance of evidence supports this approach and there is no clear benefit of larger whole brain fields. Studies addressing the appropriate volume in systematic fashion are needed. The role of dose escalation with brachytherapy and radiosurgery is limited and not supported as a standard approach. Acknowledgements We wish to acknowledge Stephen Haines, MD, Jack Rock, MD, and Tom Mikkelson, MD for their review and consultations regarding on this work. The authors also wish to express Evidentiary Table 8 continued First author/ Reference Study description Data class Conclusion Masciopinto, J. E., et al. J Neurosurg 1995 [57] Retrospective review of 31 patients with newly diagnosed GBM treated with EBRT plus SRS Follow report of Mehta et al. 1994 below III Median survival 9.5 months Two year survival 37% The authors conclude that due to limited response and local recurrence that the role of SRS in malignant glioma be carefully considered in selected patients until further study Gannett, D., B. et al. Int J Radiat Biol Phys 1995 [58] Retrospective review of 30 patients including 17 newly diagnosed GBM and 10 AA III Overall median survival 13.9 months One year survival 57% 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 study Buatti, J. M., et al. Int J Radiat Biol Phys 1995 [59] Retrospective review of 11 newly diagnosed patients (6 GBM and 5 AA) treated with EBRT and SRS III Median survival 17 months Maximum radiosurgical volume 22.5 cm3 All patients had local progression within one year of treatment The authors note the need to define appropriate patients for boost technique Mehta, M. P., J. et al. Int J Radiat Biol Phys 1994 [60] Retrospective review of 31 patients with newly diagnosed GBM treated with EBRT and SRS (of a total of 53 newly diagnosed GBM patients in same time period) III Median survival 10.5 months One year survival 38% Two year survival 28% Authors suggest that this may demonstrate improved 2 year 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 necrosis Curran et al./[54] Study applying SRS treatment criteria (KPS [ 60, 4.0 cm or less, and superficial) to the patients enrolled in RTOG 83- 02 trial (Phase I/II dose escalation) 778 total patients 89 (11%) determined to be eligible for SRS II Comparison of Median Survival by RTOG RPA Class for patient either eligible or ineligible for SRS trial: Median Survival Eligible 14.4 months Median Survival Ineligible 11.7 months (P = 0.047) Multivariate analysis indicated age, KPS, path and SRS eligibility all predictive of increased survival The authors conclude that there appeared to be a survival 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 J Neurooncol (2008) 89:313–337 335 123
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