Evidence Based Questions Flashcards
What is considered optimal surgery for glioblastoma? Which study showed evidence?
GTR improved OS in select pts compared with no clear benefit to STR
Lacroix, MDACC (J Neurosurg 2001, PMID 11780887): RR showing improved OS with ≥98% resection in better prognostic pts (young, good KPS, no MRI evidence of necrosis). GTR also limits chance of cerebral edema during RT
From a multivariate analysis of 416 patients treated at MD Anderson from June 1993 to June 1999, those with a resection of 98% or greater had a median survival of 13 months versus 8.8 months for those less than 98% (p <.0001). Another study shows benefit to gross total resection over incomplete resections with a survival advantage of 16.8 months versus 11.8 months (p <.0001), and other data have shown improvements in survival with an extent of resection as low as 70%. Chaichana KL, Jusue-Torres I, Lemos AM, et al. The butterfly effect on glioblastoma: is volumetric extent of resection more effective than biopsy for these tumors? J Neurooncol. December 2014;120(3):625–634. doi:10.1007/s11060-014-1597-9. Lacroix M, Abi-Said D, Fourney DR, et al. A multivariate analysis of 416 patients with glioblastoma multiforme: prognosis, extent of resection, and survival. J Neurosurg. 2001;95:190–198. doi:10.3171/jns.2001.95.2.0190. Stummer W, Reulen HJ, Meinel T, et al. Extent of resection and survival in glioblastoma multiforme: identification of and adjustment for bias. Neurosurgery. 2008;62: 564–576. doi:10.1227/01.neu.0000317304.31579.17.
What are the contraindications to GTR?
Eloquent/inaccessible areas involved (brainstem, motor cortex, language centers, etc.), significant infiltration past midline, periventricular or diffuse lesions, medical comorbidities
How did we arrive at the current standard RT dose? Which two studies showed doubling of survival times with adjuvant RT vs. supportive care? What ongoing trial is investigating dose esclation?
The BTCG 69-0112 and 1981 SGSG14 studies demonstrated a doubling of survival with adjuvant RT over best supportive care. Dose escalation was beneficial to 60 Gy/30 fx but there was no benefit to escalating to 70 Gy.
A subsequent University of Michigan experience showed that escalating to 90 Gy still resulted in 90% in field failures and increase in toxicity. Thus 60 Gy/30 fx is considered the standard dose for GBM.
A recent single-arm phase I study from the University of Michigan has shown promising median OS of 20.1 mos with safe dose escalation to 75 Gy/30 fx along with concurrent and adjuvant TMZ.16 This has raised the question again about the potential benefit of dose escalation in the TMZ era and has in part led to the ongoing NRG BN001 trial.
There was no benefit shown to 90 Gy using IMRT. There was also no benefit to brachytherapy in addition to conventional RT and no benefit to stereotactic radiosurgery boost (RTOG 9305). NRG-BN001 is evaluating whether hypofractionated radiation with temozolamide will improve outcomes compared to standard 60 Gy in 30 fx with temozolamide.
What chemotherapies have been used after surgery? Why are they not currently used?
Historically, nitrosoureas were utilized, until a meta-analysis of PRTs of RT versus RT+ nitrosoureas showed only modest 1-year OS benefit.
BCNU was the RTOG standard of care for many years. BCNU wafers (Gliadel®) were investigated in a phase III trial of RT +/− BCNU wafers: MS improved to 13.9 mos versus 11.8 mos However, the survival advantage was possibly driven by grade III pts, and a subsequent 2007 meta-analysis suggested BCNU wafers are not effective or cost-effective for glioblastoma.
What trial defines the current standard of care in GBM management? Inclusion cireteria of the trial? What were the two year OS for RT alone vs. chemoRT?
RT + concurrent and adjuvant TMZ is the standard of care based on the Stupp trial.
Stupp, EORTC 26899/NCIC (NEJM 2005, PMID 15758009; Lancet Oncology 2009, PMID 19269895): PRT of 573 pts with GBM, ages 18 to 70 with ECOG PS 0-2. All pts received EBRT 60 Gy/30 fx, and were randomized to RT alone or chemoRT with concurrent TMZ 75 mg/m2 d1-7 q1week then adjuvant TMZ 150 to 200 mg/m2 d1-5 q4weeks x 6c. Eighty percent received the full course; 40% received full six cycles of adjuvant TMZ. OS and PFS were significantly improved (see table, 2yr OS 10.9% vs. 27.2%)with the benefit holding across all subgroups and MGMT status as the strongest prognostic and predictive factor
Conclusion: Concurrent chemoRT and adjuvant TMZ established as standard of care for GBM.
What is the impact of MGMT status on prognosis for GBM and their response to TMZ? What publication demonstrated this?
MGMT silencing is both prognostic (better outcome regardless of treatment) and predictive (better response to a specific treatment—TMZ in this case) for GBM.
Hegi (NEJM 2005, PMID 15758010). Subset analysis of 206 GBM pts in the Stupp trial, 45% of whom had epigenetic silencing of MGMT by methylation. Regardless of TMZ use, MGMT methylation was associated with improved OS (MS 15.3 vs. 11.8 mos).
Survival in methylated pts treated with RT + TMZ versus RT alone was 21.7 mos versus 15.3 mos (p = .007) and 2-yr OS was 46% versus 23%, p = .007. In nonmethylated pts, the MS difference between the groups was NS (12.7 vs. 11.8 mos); however, 2-yr OS was significant (13% vs. 2%).
Hegi tested the relationship of MGMT (O6-methylguanine-DNA methyltransferase—repair enzyme) silencing by methylation and survival from the Stupp study. Methylation of MGMT promoter: 2-year OS = 46% in temozolomide arm versus 22.7% in RT alone arm (p = .007 by the log-rank test). Unmethylated MGMT promoter: 2-year OS = 13.8% in temozolomide arm versus less than 2% in RT alone arm. Based on the results of this study, RTOG 0525 randomized patients with GBM to conventional adjuvant temozolomide dosing per EORTC-NCIC trial versus a dose-dense regimen of 100 mg per meter squared days 1 to 21 per 28-day cycle.
Is there any benefit to increasing the dose density of TMZ? Which trial demonstrated this?
MGMT methylation is prognostic, but dose-dense TMZ was not beneficial.
Gilbert, RTOG 0525 (JCO 2013, PMID 24101040): PRT of 833 pts treated 60 Gy/30 fx with daily TMZ (75 mg/m2) randomized to adjuvant Stupp regimen (150–200 mg/m2 × 5 days) versus adjuvant TMZ 75–100 mg/m2 × 21 days q4w × 6–12 cycles.
Increasing the number of days that pts received TMZ did not improve OS or PFS, regardless of methylation status. However, the study did confirm the prognostic significance of MGMT methylation, with improved OS (21.2 vs. 14 mos, p < .0001).
RTOG 0525 compared two dosing schemes. The standard regimen based on the Stupp study was compared to a dose-dense regimen. Standard arm: 60 Gy XRT + TMZ 75 mg/m2 qd → TMZ 150 mg × 1 w/dose escalation to 200 mg/m2 d1–5 q4w × 6–12. Experimental arm: 60 Gy XRT + 75 mg/m2 × 1 w/dose escalation to 100 mg/m2 d1–21 of 28–day cycle × 6–12. No survival benefit was seen.
Is there any role of hyperfractionation in GBM? Which trials investigated this?
RTOG 8302 and RTOG 9006 examined this question and showed no benefit to hyperfractionated RT compared to standard fractionation in pts with malignant glioma
RTOG 83-02 was a phase I/II trial of hyperfractionation of 1.2 Gy BID or accelerated hyperfractionation of 1.6 Gy BID 72 Gy at 1.2 Gy BID was found to have the best median survival with the least toxicity. RTOG 90-06 and other studies failed to show a benefit to altered fractionation.
Does radiosurgery boost improve disease control for GBM? Which trial investigated this?
There is no role for an upfront SRS boost in GBM.
Souhami, RTOG 9305 (IJROP 2004, PMID 15465203): PRT of GBM pts with KPS ≥70 and unifocal, enhancing, well-demarcated, ≤3 to 4 cm lesion randomized to RT + BCNU +/− upfront SRS (15–24 Gy, depending on size). MS was 13.5 mos in SRS arm versus 13.6 mos in standard arm.
Is there a role for a brachytherapy boost in malignant gliomas?
There is no OS benefit to brachytherapy boost.
Two PRTs were negative: (a) 50 Gy/25 fx +/− I-125 implant (60 Gy). MS 13.8 versus 13.2 mos; (b) upfront 125I seeds (60 Gy) + 60.2 Gy/35 fx EBRT with concurrent BCNU versus EBRT + BCNU alone. No difference in OS. In GBM subset, MS 64 weeks versus 58.1 weeks.
What is the role of whole brain radiation therapy (WBRT) in GBM?
WBRT can be considered for multifocal disease/subependymal spread, or poor performance pts (KPS <60). Comparable outcomes (MS ~7 mos) to limited volume RT
What is the basis for the treatment volumes used during standard chemoRT?
After standard treatment, over 80% of recurrences occur within a 2-cm margin of the contrast-enhancing lesion seen on CT or MRI at original diagnosis. Thus high-dose treatment volume typically includes a 2-cm CTV expansion of the resection cavity and any residual enhancing tumor, as used in RTOG protocols. Though peritumoral edema seen on T2 and FLAIR MRI sequences are typically targeted in the low-dose PTV, retrospective single institution reviews have suggested that there are no increased rates of local recurrence when peritumoral edema is not specifically targeted during radiation treatment. In fact, EORTC protocols for GBM do not include targeting of edema volumes.
Is there a benefit to the addition of bevacizumab to TMZ? Which trials investigated this? What were complications in the bevacizumab arm?
No improvement in OS with addition of bevacizumab to standard RT + TMZ; there was a modest PFS benefit but this did not reach predefined target for statistical significance.
Gilbert, RTOG 0825 (NEJM 2014, PMID 24552317): PRT in 637 GBM pts treated with the Stupp regimen with or without bevacizumab 10 mg/kg q2 weeks x 12 cycles after RT. Pts were stratified by MGMT methylation status. Prespecified coprimary endpoints were OS and PFS. Use of bevacizumab did not improve MS (15.7 vs. 16.1 mos). Although PFS was increased with use of bevacizumab (10.7 vs. 7.3 mos, p = .007), this did not meet the prespecified endpoint of p < .004. Bevacizumab group also associated with increased hypertension, VTE events, intestinal perforation, neutropenia.
Chinot, AVAGLIO Study (NEJM 2014, PMID 24552318): PRT of 921 pts with GBM treated with Stupp regimen with or without biweekly bevacizumab 10 mg/kg q2 weeks. OS was not statistically improved 16.8 versus 16.7 mos (hazard ratio [HR 0.88], p = .10). PFS was statistically improved to 10.6 from 6.2 mos with addition of bevacizumab. However, higher grade III toxicity was observed in the bevacizumab arm 66.8% versus 51.3%.
What are tumor treating fields (TTF) and is there a benefit in GBM? Which trial investigated this? What were in the OS in treated vs untreated groups?
Polarization occurs in cells during the spindle formation process in mitosis. Alternating electric fields can be used to disrupt this normal polarization, thus inhibiting cell division. The FDA-approved NovoTTF-100A (Optune®) is a device that a pt wears on his or her head along with an attached portable battery pack that emits alternating electric fields. Despite the positive trial results as in the following, it is currently expensive and can also be difficult for pts, as it must be worn for most of the day.
Stupp (JAMA 2015, PMID 26670971): PRT of 695 pts with GBM treated with chemoRT (Stupp regimen) who were then randomized to either conventional adjuvant TMZ or TTF + TMZ. Preplanned interim analysis of 315 pts with a MFU of 38 mos demonstrated significantly improved OS (20.5 mos vs. 15.6 mos p = .001) and PFS (7.1 mos vs. 4.0 mos, p= .001) with use of TTF + TMZ.
Conclusion: When NovoTTF is added to adjuvant TMZ as part of Stupp protocol, it is associated with a 5-month OS benefit, though this is an interim analysis and further follow-up is needed. Based on interim analysis, further enrollment to the trial was discontinued (695 of planned 700 pts enrolled at time of termination).
Using a method of electric field production that is hypothesized to interfere with mitotic spindle formation, TTF devices have been shown to improve survival on the EF-14 study. Specifically, after completing tumor debulking and standard chemoradiation, patients were randomized to adjuvant temozolomide versus TTF and temozolomide. Patients on the TTF arm had improved survival compared to the standard arm at 2 years (43% vs. 31%), 3 years (26% vs. 16%), 4 years (20% vs. 8%), and 5 years (13% vs. 5%).
Stupp R, Taillibert S, Kanner A, et al. Effect of tumor-treating fields plus maintenance temozolamide vs maintenance temozolamide alone on survival in patients with glioblastoma: a randomized clinical trial. JAMA. 2015;314(23):2535–2543.
What is the role of RT over best supportive care? Which trial investigated this? What were the MS in each group? Was QOL improved?
Radiation therapy improves OS over best supportive care in elderly pts with good KPS.
Keime-Guibert, France (NEJM 2007, PMID 17429084): PRT of 81 pts ≥age 70 (all KPS ≥70) with newly diagnosed AA or GBM randomized to RT 50.4 Gy/28 fx versus best supportive care after biopsy/resection. MS was improved with RT (29.1 vs. 16.9 weeks, p = .002). There was no difference between the arms in terms of QOL or cognition. The trial was closed early after interim analysis demonstrated improved OS with use of RT.
Keime-Guilbert reported on 85 patients enrolled in a study comparing supportive care alone versus radiation to 50.4 Gy at 1.8 Gy/fx. Radiation improved overall survival from 16.9 weeks to 29.1 weeks (p = .002). Quality of life and cognitive evaluation did not differ between the groups.
