CNS Flashcards
What was the patient population studied in Patchell I (NEJM 1990)?
Single brain mets (n=48)
What was the regimen studied in Patchell I?
→resection + WBRT 36 Gy<br></br>vs.<br></br>→biopsy + WBRT 36 Gy
What were the results of Patchell I?
Surgery added to WBRT improved survival<br></br>and LC.<div><br></br>Median OS <b>40 wks</b> vs. <i>15 wks.</i></div><div><br></br>LC <b>80%</b> vs. <i>48%</i> (crude).</div>
What trial demonstrated that addition of surgery to WBRT forsolitary mets results inimproved OS, reduced LR, andimproved QOL?
”"”Patchell I”” University ofKentuky.<div>Patchell et al,NEJM, 1990<br></br></div>”
What was a criticism of Patchell 1?
11% that were randomized were found to not havemetastatic tumors. These were not included in analysis. The original result was phrased as LR (20% vs. 52%), butis now modified to LC to make parallel to other trials andto avoid framing bias. LC of 48% with WBRT seems low.
What was the patient population studied in Patchell 2?
Single brain mets s/pcomplete resection (n=95)?
<div>What was the regimen studied in Patchell 2?</div>
s/p complete resection→<div><br></br>→WBRT 50.4 Gy/28 fx<br></br>vs.<br></br>→observation</div>
What were the results of Patchell 2?
“-WBRT after surgery reduces recurrence andneurologic death, but <b><i>no change in OS.</i></b><div><br></br>-Median OS 48 wks vs. 43 wks (NS)</div><div><br></br>-neurologic death 14% vs. 44%</div><div><br></br>-LC 90% vs. 54%</div><div><br></br>-Total brain control 82% vs. 30%</div>”
Which study demonstrated that WBRT for solitary mets resultsin improved LC and reducedneurologic death?
Patchell 2.<div>Caveat was no change in OS.</div>
What was the WBRT dose used in Patchell 2?
50.4Gy/28 fx.<div>Higher than modern dose.</div>
What was the patient population used in RTOG 6901 and 7361?
Brain mets (n=1830)
What was the regimen studied in RTOG 6901 & 7361?
WBRT dose escalation:<div><br></br>30 Gy/ 10 fx → 30/15 → 40/15 →40/20</div><div><br></br>20/5 → 30/10 → 40/15</div>
What were the results of RTOG 6901 & 7361?
-No difference in OS (18 weeks for first study, 15 weeks for 2nd)<div><br></br>-OS with 40/15 trended to better inambulatory lung, p=0.07 and p=0.02 foreach study<br></br><br></br></div><div>-Better OS with 40/15 in lung brain mets only<br></br><br></br></div><div>-No difference in symptom improvement</div>
Which trials demonstrated there is no difference insymptom response or OSbetween WBRT dose escalation schedules(except in some populations that showed 40/15 seemed to trend tobetter OS)?
RTOG 6901 & 7361
What was the patient population studied in NRG-CC001 trial?
Brain metastases (n=518)
What was the regimen studied in NRG-CC001?
→WBRT 30 Gy/10 fx<br></br>vs.<br></br>→hippocampal avoidance IMRT<br></br>WBRT 30 Gy/10 fx<div><br></br><i>Memantine in both arms</i></div>
What were the results of NRG-CC001?
- Hippocampal sparing RT led to lessdeterioration in executive function andlearning and memory.<div><br></br></div><div>- Also improved fatigue, difficulty speaking,remembering, interference in dailyactivities, and less cognitive symptoms.</div><div><br></br></div><div>- Hippocampus D100% <9-10 Gy was bestdosimetric factor correlated with outcome.</div>
What trial demonstratred improved cognitive function with hippocampal avoidance RT?
NRG-CC001<div><br></br></div><div>Brown et al,JCO, 2020<br></br></div>
<div>What was the patient population studied in QUARTZ trial?<br></br></div>
NSCLC with brainmetastasis unsuitablefor surgery or SRS (n=538)<div><br></br></div><div><br></br>Characteristics:<br></br>≥5 mets in ~33%<br></br>4 in <10%<br></br>3 in ~10%<br></br>2 in 20%<br></br>1 in 30%</div>
<div>What was the regimen studied in QUARTZ?</div>
Noninferiority<div><br></br>→WBRT 20 Gy/5 fx<br></br>vs.<br></br>→no RT</div><div><br></br>Primary endpoint: QALYs</div><div>Supportive care and <b>DEXAMETHASONE</b> in both<br></br>arms</div>
<div>What were the results of QUARTZ trial?</div>
“-QALYs noninferior<br></br>-Median OS ~2 mos, not different<br></br>-No difference in QOL or dex use<div><br></br>-On subanalysis, those with ≥5 metastatsis did show OS benefit from WBRT.</div><div><br></br>There was some trend to OS benefit ifprimary controlled, no extracranial mets, or higher GPA.</div>”
<div>What trial demonstrated WBRT for palliation of brain mets is noninferior to observation in QALY outcomes in these poor prognosis patients?</div>
QUARTZ<div><div>Although, on subanalysis OS favors WBRT for ≥5 mets or age <60?</div></div>
<div>What was the patient population studied in EORTC 22952-26001trial?</div>
1-3 brain mets <3.5cm,<div>Controlledextracranial disease,</div><div>PS0-2</div><div><br></br></div><div>(n=359)</div>
<div>What was the regimen studied in EORTC 22952-26001?</div>
Complete surgery or SRS →<div><br></br>→obs<br></br>vs.<br></br>→WBRT 30 Gy</div>
<div>What were the results of EORTC 22952-26001?</div>
•HRQOL worse with WBRT<div><br></br>•Time to worse performance statusunchanged, 11.7 mos vs. 9.5 mos</div><div>•OS similar, ~10.8 mos mos (NS)<br></br>•Neuro death improved with WBRT: 44% vs. 28% WBRT<br></br><br></br></div>
What were the 2-yr LC with surgery and SRS vs WBRT?
<div>2-yr LC surgery: 41% obs vs. 72% WBRT<br></br></div>
<div><br></br></div>
2-yr LC SRS: 69% obs vs. 81% WBRT<div><br></br><div>Intracranial progression 44% vs. 28%<br></br>Subanalysis shows that surgery and SRS are similar in outcomes.</div></div>
<div>What trial demonstrated WBRT after surgery or SRS in limited mets reduces LR but does not improve QOL or OS?</div>
EORTC 22952-26001
<div>What was the patient population studied in JSROG trial?</div>
1-4 brain mets <3cm<div><br></br></div><div>n=132</div>
<div>What was the regimen studied in JSROG?</div>
→SRS<br></br>vs.<br></br>→SRS+WBRT 30 Gy/10 fx<div><br></br>SRS dose 18-25 Gy for SRS alone.<br></br>Dose reduced 30% if with WBRT</div><div><br></br>MMSE used to measure cognitive<br></br>function</div>
<div>What were the results of JSROG trial?</div>
•WBRT decreased recurrence but noimprovement in OS or neuro death.<br></br>•Median OS 8.0 mos vs. 7.5 WBRT+SRS (NS)<div><br></br>•1-yr OS 28% vs. 39% (NS)<br></br>•No diff in toxicity, neuro function<br></br><br></br></div>
<div>What trial demonstrated SRS alone without WBRT in limited mets resulted in increased brain tumor recurrence but no change in OS or neurologic death?</div>
JSROG (Aoyama et al, JAMA 2006 and 2015)
<div>What was the patient population studied in MDACC (Chang et al, Lancet Oncol, 2009) trial?</div>
1-3 brain mets<div>n=58</div>
What was the regimen studied in MDACC (Chang et al, Lancet Oncol, 2009)?
→SRS<br></br>vs.<br></br>→SRS+WBRT 30 Gy/12 fx<div><br></br>Primary endpoint: neuro functionper HVLT-R</div>
What were the results of MDACC (Chang et al, Lancet Oncol,2009) trial?
•Terminated early: SRS+WBRT showed worse neuro decline at 4 months. LC improved with WBRT, but not OS<br></br><br></br><div>•Neuro decline: SRS alone 24% vs. 52%SRS+WBRT</div><div><br></br></div><div>•OS worse with WBRT, 15 mos vs. 6 mos</div>
What trial demonstratedworse neurodecline and worse OS with the addition of WBRT to SRS in limitedmets?
MDACC (Chang et al,Lancet Oncol,2009)
<div>What was the patient population studied in Alliance N0574 trial?</div>
1-3 brain mets<div>(n=213)</div>
What was the regimen studied in Alliance N0574?
→SRS <br></br>vs. <br></br>→SRS+WBRT 30 Gy/12 fx<br></br><br></br>SRS dose 18-22 Gy in SRS+WBRT<br></br>and SRS dose 20-24 Gy for SRS alone
<div>What were the results of Alliance N0574?</div>
-Median OS: 10.4 mos vs. 7.4 mos (p=.92)<div><br></br>-12-mo LC 73% vs. 90% with WBRT<br></br>-12-mo total brain control 51% vs. 85%<br></br>-Time to recurrence shorter with SRS<br></br><br></br>No effect of DS-GPA on OS<br></br><br></br></div>
What trial demonstrated SRS without WBRT in limited mets results in less neuro decline?
<div>Alliance N0574.</div>
Tumor reccurence is increased somewhat without WBRT but without change in OS.
<div>What was the patient population studied in RTOG 9508 trial?</div>
1-3 mets<div><br></br></div><div>(n=333)</div>
<div>What was the regimen studied in RTOG 9508?</div>
“<span>→WBRT 37.5 Gy <br></br></span>vs. <br></br>→SRS+WBRT<span><br></br><br></br>SRS dose per RTOG 9005:<br></br>24 Gy size ≤2.0 cm<br></br>18 Gy size >2 to ≤3cm<br></br>15 Gy size >3 cm</span>”
<div>What were the results of RTOG 9508?</div>
“<span>Addition of SRS to WBRT improved LC and KPS but no change in OS</span><br></br>1-yr LC 71% WBRT vs. 82% SRS+WBRT<br></br><br></br><div><br></br>•On MVA of all patients in both arms, RPA 1 and NSCLC histology had better OS (regardless of treatment arm)<br></br>•Median OS 5.7 mos SRS vs. 6.5 mos (NS)</div>”
What trial demonstrated adding an SRS boost to WBRT in limited mets improves LC?
RTOG 9508
<div>What was the patient population studied in RTOG 9005 trial?</div>
Recurrent primary or recurrent brain tumors s/p prior WBRT<div><br></br></div><div>(n=156)</div>
<div>What was the regimen studied in RTOG 9005?</div>
“Phase I Dose escalation in 3 Gy increments, beginning at:<br></br>18 Gy for ≤2 cm<br></br>15 Gy for 2-3 cm<br></br>12 Gy for 3-4 cm<br></br>Grade 3-5 toxicity defined as limiting.<br></br><br></br><span>All had previous WBRT (range 30-60 Gy).</span> LINAC and GammaKnife allowed. Dose to 50-90% isodose line.”
<div>What were the results of RTOG 9005?</div>
Max tolerated doses: 18 Gy for 21-30 mm and 15 Gy for 31-40 mm. 24 Gy for ≤20 mm was the highest evaluable dose but may not be MTD; Investigators declined to escalate to 27 Gy in ≤2 cm.<br></br><br></br>Diameter associated with neurotoxicity.
<div>What trial demonstrated max tolerated doses in SRS for brain mets: 24 Gy for ≤20 mm, 18 Gy for 21-30 mm, and 15 Gy for 31-40 mm?</div>
RTOG 9005
What trial established SRS dosing following WBRT for later trials?<div>(Hint: Phase I dose escalation in 3 Gy increments)</div>
“RTOG 9005<div><br></br></div><div><span>Prior WBRT in all patients. </span>Established dosing for later trials. This is a phase I toxicity study and was not powered for LC. On a MVA dose was not associated with LC: lower doses may have just as effective LC. (The authors did a rudimentary LC analysis looking at GK and Linac, but arms are too imbalanced to draw conclusions.) 36% were primary tumors, 64% were mets.<br></br></div>”
“<div>What was the patient population studied in MDACC (<a>Li et al, ASTRO, 2020</a>)?</div>”
4-15 brain metastases, non-melanoma<div><br></br></div><div>(n=72)</div>
“What was the regimen studied in MDACC (<a>Li et al, ASTRO, 2020</a>)?”
→SRS<br></br>vs. <br></br>→WBRT (62% had memantine)<br></br><br></br>Neurocognitive testing
“What were the results MDACC (<a>Li et al, ASTRO, 2020</a>)?”
Cognitive function is better with SRS<br></br><br></br>Median OS 8-10 mos, p=0.45<br></br>Distant brain failure 4.2 mos vs. 18.1 mos<br></br>LC 100% vs. 95.5%
<div>What trial demonstratedSRS for 4-15 brain metastasis has unchanged OS compared to WBRT and superior cognitive function with SRS?</div>
“MDACC (<a>Li et al, ASTRO, 2020</a>)”
<div>What was the patient population studied inMount Sinai, NY (Lehrer et al, IJROBP, 2019)?</div>
<br></br>
(n=1887) brain metsSRS to large brain mets
<div>What was the regimen studied in Mount Sinai, NY (Lehrer et al, IJROBP, 2019) meta trial?</div>
“Meta-analysis of 24 studies of <span>single and multi fx SRS to brain</span> mets. Evaluates radiation necrosis and LC<br></br><br></br>Various doses and fractionation regimens used”
What were the results of Mount Sinai, NY (Lehrer et al, IJROBP, 2019) meta trial?
“<span>LC in size 4-14 cc (2-3 cm) definitive<br></br></span>•single fx 78% vs. multi 93%, p=0.18<div><br></br><span>LC in size >14 cc (>3cm) definitive<br></br></span>•single fx 78% vs. multi 79%, p=.76</div><div><br></br><span>LC in size >14 cc (>3cm), post op<br></br></span>•single fx 62% vs. multi 86%, p=0.13<br></br><br></br></div>”
<div>What trial demonstrateda reduction in radiation necrosis with multi fx RT in tumors size 4-14 cc, about 2-3 cm diameter?</div>
Mount Sinai, NY (Lehrer et al, IJROBP, 2019) meta trial
<div>What was the patient population studied in N107C/ CEC.3/ RTOG 1270?</div>
1-4 brain metastases and resection of 1 lesion. STR allowed (77%% had single met, ~10% STR)<br></br><br></br>Resection cavity <5 cm and unresected lesions ≤3.0 cm<div><br></br></div><div>(n=194)</div>
<div>What was the regimen studied in N107C/ CEC.3/ RTOG 1270?</div>
“<span>→SRS to cavity </span><br></br>vs. <br></br>→WBRT to 30 or 37.5 Gy <br></br><br></br>Unresected lesions treated with SRS in both arms<br></br>”
<div>What were the results of N107C/ CEC.3/ RTOG 1270?</div>
“<span>Worse LC in cavity with SRS<br></br>12-mo cavity LC 61% vs. 81% (supp data)</span><span><br></br></span><span>12-mo distant brain control 65% vs. 89%<br></br></span><br></br>Median OS ~12 mos, not different<br></br><span><br></br>-Better cognitive deterioration free survival with SRS</span>, median 3.7 mos vs. 3.0 mos<br></br><br></br><br></br><br></br>”
In N107C/ CEC.3/ RTOG 1270, how did the 30Gy regimen compare to the 37.5 Gy WBRT regimen?
“<span>30 Gy and 37.5 Gy compared: </span><br></br><span>-More grade ≥3 toxicity with 37.5 Gy<br></br></span>-No difference in cognitive failure (p=0.64).<div><br></br></div><div><br></br></div><div><br></br></div><div>Some trend to benefit in cavity LC (p=0.14), cranial control (p=0.09), and OS (p=0.18) with 37.5 Gy</div>”
<div>What trial demonstrated :</div>
<div>a) SRS alone leads to unchanged OS compared to WBRT alone</div>
<div>b) WBRT has better LC</div>
<div>b) QOL is improved with SRS?</div>
“N107C/ CEC.3/ RTOG 1270<div><span><a>Brown et al, Lancet Oncol, 2017<br></br>Trifiletti et al, ASTRO, 2019</a></span><br></br></div><div><br></br></div>”
<div>What was the patient population studied in JCOG 0504?</div>
“1-4 brain metastasis and <span>resection of all, GTR or STR </span>(73% had single met)<span><br></br></span><br></br>One lesion >3 cm allowed<div><br></br></div><div>(n=271)</div>”
What was the regimen studied in JCOG 0504?
“Resection of <span>all</span> brain mets →<br></br><br></br>→SRS to cavity for STRs, observe GTRs (termed ““salvage SRS””)<br></br>vs. <br></br>→WBRT 37.5 Gy<span><br></br><br></br>40% in SRS arm had STR and SRS; 60% had GTR and obs<br></br></span><br></br>SRS doses: 24 Gy for ≤4 cc, 18 Gy for >4 cc”
<div>What were the results of JCOG 0504?</div>
“-Cavity LC 51% vs. 78% (WBRT)<br></br>-Median OS 15.6 mos, not different<div><br></br><span>Grade 2-4 cognitive toxicity 7.7% vs. 16.4% (WBRT)</span></div>”
What trial demonstrated that SRS for STR only in resected brain mets is noninferior compared to WBRT in OS although LR is increased?
“JCOG 0504<a>Kayama et al, JCO, 2017</a>”
“What were the criticisms of JCOG 0504<a>Kayama et al, JCO, 2017</a>?”
This study requires resection of all brain mets. SRS was given only when resection was subtotal (40%), but not for GTR (60%), which may explain the poor LC in this study. <br></br><br></br>WBRT was 15 fractions (higher BED than 30 Gy in 10 fx).
<div>What was the patient population studied inMDACC (Mahajan et al, Lancet Oncol, 2017)?</div>
1-3 brain metastases and GTR of ≥1 lesion (~62% had single met)<br></br><br></br>Resection cavity ≤4 cm and unresected lesions ≤3 cm<div><br></br></div><div>n=131</div>
<div>What was the regimen studied in MDACC (Mahajan et al, Lancet Oncol, 2017)?</div>
“<span>→SRS to cavity</span><br></br>vs. <br></br>→Obs to cavity <br></br><br></br>Unresected lesions treated with SRS in both arms<br></br><br></br>SRS doses: 16 Gy for ≤10 cc, 14 Gy for >10.1-15 cc, 12 Gy for >15 cc”
What were the results of MDACC (Mahajan et al, Lancet Oncol, 2017)?
“<span>LC improved with SRS over obs<br></br>12-mo cavity LC 72% vs. 43% (obs)</span><br></br>Median OS 17 mos, not different<br></br>”
<div>What trial demonstratedpostoperative SRS is effective at the reduction of LF and may be considered as an alternative to WBRT?</div>
Mahajan, MDACC (Lancet Oncol 2017)
What is theRTOG Recursive Partitioning Analysis (RPA) prognostic system?
“<img></img>”
What is the revised diagnosis-specific GPA (Graded Prognostic Assessment)?
“Most recent multi-institutionalretrospective cohort, more modern than the RPA and less subjective<div><br></br></div><div><img></img><br></br></div>”
“<div>What were the results of the 3 BTSG trials for malignant glioma (86% GB, n=621;<a>Walker et al, IJROBP, 1979</a>)?</div>”
“Median OS: <span>18 wks for no RT</span>, 28 wks for 50 Gy, 36 wks for 55 Gy, and <b>42 wks for 60 Gy.</b><br></br><br></br>KPS was biased against the ≤45 Gy, group - more died in that group before completing therapy”
<div>What was the patient population studied in EORTC 26899 (Stupp et al, NEJM, 2005<br></br>Hegi et al, NEJM, 2005, Stupp et al, Lancet Oncol, 2009)?</div>
PRT of 573 pts with GBM, ages 18 to 70 with ECOG PS 0-2.<div><br></br></div><div>MGMT was methylated in 45%</div>
<div>What was the regimen studied in Stupp EORTC 26899/NCIC?</div>
“<span>→60 Gy + conc TMZ & adj TMZ x6<br></br></span>vs. <br></br>→60 Gy <span><br></br><br></br></span>Later analysis evaluated effect of MGMT methylation”
<div>What were the results of Stupp EORTC 26899/NCIC?</div>
Improved OS with TMZ. <br></br>Median OS 14.6 mos vs. 12.1 mos<div><br></br>2-yr OS 26.5% vs. 10.4%. <br></br>5-yr OS 10% vs. 2%<br></br><br></br></div>
How were the outcomes of Methylated MGMT vs Unmethylated MGMT GBM patients differ in Stupp EORTC 26899/NCIC?
“Adding TMZ to RT results in OS benefit. Only those with a methylated MGMT promoter benefitted, though there was trend to benefit without methylation.<div><br></br><span>Methylated MGMT:</span><br></br>Median OS 22 mos TMZ vs. 15 mos<br></br>2-yr OS 46% vs. 23%<br></br>5-yr OS 14% vs. 5%<br></br><br></br><span>Unmethylated MGMT:</span><br></br><span>Median OS 12.7 vs. 11.8 mos (p=0.06)</span><br></br>2-yr OS 14% vs. 2%<br></br>5-yr OS 8% vs. 0</div>”
<div>What was the patient population studied in CeTeG / NOA-09 (Herrlinger et al, Lancet, 2019)?</div>
“Glioblastoma with <span>methylated MGMT</span><div><span><br></br></span></div><div>n=141</div>”
<div>What was the regimen studied in CeTeG / NOA-09?</div>
“→60 Gy + conc & adj TMZ<br></br>vs.<br></br><span>→60 Gy + TMZ + lomustine</span>”
<div>What were the results of CeTeG / NOA-09?</div>
“Median OS 31<span> vs. 48 mos (ITT) (+Lomustine group)</span><br></br>Median OS 30 vs. 40 mos per protocol <br></br>”
<div>What trial demonstrated improved OS with the addition of lomustine to TMZ and RT in GB with methylated MGMT?</div>
CeTeG / NOA-09<div>Herrlinger et al, Lancet, 2019</div><div><br></br></div><div>The trial may be underpowered. The modifed ITT analysis leads to patients being excluded and even lower power. Some call for a multi-institutional trial with larger numbers (Stupp 2019). It is unclear how there can be a change in OS without a change in PFS. Perhaps lomustine has a later effect, or lomustine creates more pseudoprogression that was called progression. There were some small differences in 2nd line therapies but not major.<br></br></div>
<div>What was the patient population studied in EF-14 (Stupp et al, JAMA, 2015; Kesari et al, SNO, 2015; Stupp et al, JAMA, 2017)?</div>
315 newly diagnosed glioblastoma<div>Optune tumor TTF trial</div>
<div>What was the regimen studied in EF-14 (Stupp et al, JAMA, 2015; Kesari et al, SNO, 2015; Stupp et al, JAMA, 2017)?</div>
“RT + conc TMZ →<br></br><br></br><span>→adjuvant TMZ + tumor treating fields (until 2nd progression or 2 years)<br></br></span>vs.<br></br>→adjuvant TMZ”
What were the results of EF-14 (Stupp et al, JAMA, 2015; Kesari et al, SNO, 2015; Stupp et al, JAMA, 2017)?
“<span>OS improved with TTF</span><br></br>Median OS 20.9 mos vs. 16.0 mos<br></br><span>2-yr OS 43% vs. 31%<br></br></span>Median PFS 6.7 vs. 4.0 mos<div><br></br><span>On subanalysis, benefit present in any MGMT status, any age</span><br></br></div>”
What trial demonstrated NovoTTF is associated with a 5-month OS benefit when added to adjuvant TMZ as part of Stupp protocol?
<b>EF-14 (Stupp et al</b>, JAMA, 2015; Kesari et al, SNO, 2015; Stupp et al, JAMA, 2017)<div><br></br></div><div><br></br></div><div>Tumor treating fields (TTF) mechanism: low amplitude alternating electric fields that disrupt cell division and organelles. Required to wear ≥18 hrs in protocol.<br></br><br></br>Sharp dropoff of treatment effect if device worn <50% of time. At 75% of time (18 hours), a greater benefit occurs.<br></br></div>
What was the patient population studied in RTOG 0825?
Glioblastoma<div><br></br></div><div>n=978</div>
What was the regimen studied inRTOG 0825?
60 Gy + TMZ →<br></br><br></br>→bevacizumab <br></br>vs. <br></br>→placebo<br></br><br></br>Bev started at week 4 during RT and continued as maintenance<br></br><br></br>Crossover allowed if disease progression
What were the results of RTOG 0825?
“<span>No change in OS</span>: 15.7 vs. 16.1 mos<br></br>PFS longer with bev: 10.7 mos vs. 7.3 mos<div><br></br>•Adverse effects higher in bev group: hypertension, thromboembolism, intenstinal perf, neutropenia, decline in QOL and cognitive function<br></br>•Those with Pro-B type (indicative of proneural) had improved PFS, but not OS. But non-Pro B type had worse OS</div>”
What trial demonstrated bevacizumab improves only PFS without benefit in OS while increasing toxicity, including cognitive?
<div>RTOG 0825</div>
<div><br></br></div>
PFS may be a result of vascular changes and not tumoricidal effects.<div>Some say lack of OS benefit was due to crossover, but note that median OS without bev is nearly identical to EORTC Stupp trial outcome and a direct comparison is not possible (Stupp 2009). Bevacizumab also failed to show OS benefit in a randomized trial in recurrent GB (Wick 2017).<br></br></div>
What was the patient population studied in EORTC 26062/TROG/CCTG?
“Glioblastoma <span>age ≥65</span>”
What was the regimen studied in EORTC 26062/TROG/CCTG?
“<span>→40 Gy/15 fx + conc and adjuvant TMZ <br></br></span>vs. <br></br>→RT alone 40 Gy/15 fx”
What were the results of EORTC 26062/TROG/CCTG?
“<span>Median OS and PFS improved with TMZ</span><br></br>Median OS 9.3 mos vs. 7.6 mos<br></br>Median PFS 5.3 mos vs. 3.9 mos<div><br></br>Methylated MGMT median OS 13.5 mos vs. 7.7 mos—->statistically significant<br></br>Un-methylated MGMT median OS 10.0 mos vs 7.9 mos—->NOT statistically significant</div>”
What trial demonstrated an OS benefit with the addition of TMZ in elderly GM patients<br></br>receiving a hypofractionated RT?
EORTC 26062/TROG/CCTG?<div><br></br></div><div>Pts with MGMT methylation benefit most fromRT + TMZ with a ~6-month improvement in OS.<br></br></div>
What trial demonstrated TMZ alone is a noninferior option compared to standard RT in elderly pts and may be preferred<br></br>over RT alone in pts with MGMT promoter methylation?
“<b>NOA-08 (Wick,Lancet Oncology 2012)</b><div><br></br></div><div>TMZ was noninferior to RT in elderly or poor KPS GB. TMZ is ideal for methylated MGMT and RT is ideal for unmethylated MGMT.<br></br></div><div><br></br></div><div><span>RT and TMZ noninferior: <br></br>OS 9.6 mos vs. 8 mos</span><br></br>-With MGMT methylation, longer EFS with TMZ: 8.4 vs. 4.6 mos<br></br>-With no MGMT methylation, outcomes poor but RT better: 4.6 vs. 3.3 mos<br></br></div>”
What was the patient population studied in Malmström, Nordic Trial (Lancet 2012)?
High grade glioma in age ≥60<div>n=342</div>
What was the regimen studied inMalmström, Nordic Trial (Lancet 2012)?
→60 Gy/30 fx <br></br>vs. <br></br>→34 Gy/10 fx <br></br>vs. <br></br>→TMZ alone
What were the results ofMalmström, Nordic Trial (Lancet 2012)
MS was significantly improved for pts<br></br>receiving TMZ alone (8 mos) versus standard RT (6 mos) but not versus hypofractionated<br></br>RT (7.5 mos).
What was the patient population studied in Roa, Canadian (JCO 2004)?
GBM, age ≥60 and KPS≥50<div><br></br><div>n=100</div></div>
What was the regimen studied in Roa, Canadian (JCO 2004)?
→60 Gy/30 fx <br></br>vs. <br></br>→40 Gy/15 fx
What were the results of Roa, Canadian (JCO 2004)?
MS was 5.1 mos for standard (60Gy/30) versus 5.6 for shorter course RT (40Gy/15) (p = NS)<div><br></br></div><div>26% pts stopped long-courseRT versus 10% in short-course arm<br></br></div>
What trial demonstrated no difference in OS between 40 Gy/15 fx and standardfractionation in pts older than 60 who are not receivingsystemic therapy?
Roa, Canadian (JCO 2004)
What was the patient population studied in Roa, IAEA (JCO 2015)?
GBM + age ≥50, KPS 50-70, or age ≥65 KPS 50-100<div>n=98</div>
What was the regimen studied inRoa, IAEA (JCO 2015)?
→25 Gy/5 fx <br></br>vs. <br></br>→40 Gy/15 fx
What were the results ofRoa, IAEA (JCO 2015)?
Pts receiving 25 Gy/5 fx had noninferior OS compared to those receiving 40 Gy/15fx, and no difference in PFS or QOL.<div><br></br></div><div>Conclusion: Short-course RT delivered in 1 week (25Gy/5 fx) is a treatment option for elderly and/or frail pts with newly diagnosed GBM.</div>
What trial demonstrated improves OS with RT over best supportive care in elderly GBM pts with good KPS?
Keime-Guibert, France (NEJM 2007)<div><br></br></div><div>Median OS 7.3 mos RT (50 Gy/28 fx) vs. 4.3 mos<br></br>No diff in QOL or cognition<br></br></div>
What trial established 11 Gy x 3 fx as the maximum tolerated dose for single site small size recurrent GBM treated with RT?
MSKCC Clarke et al, IJROBP, 2017<div><br></br><div>Recurrent glioblastoma or anaplastic astrocytoma, size ≤40cc; Phase 1 with 15pts<br></br><br></br></div><div>SRT delivered to GTV plus 2-5 mm PTV margin<br></br></div></div>
What phase III trial demonstrated no OS benefit but improvement in PFS with addition of bevazicumab to lomustine?
EORTC 26101(Wick et al, NEJM, 2017)<div><br></br></div><div>→lomustine plus bevacizumab <br></br>vs. <br></br>→lomustine alone<br></br></div><div><br></br></div><div>in first progression of GBM</div>
What was the patient population studied inRTOG 9402 Cairncross et al (JCO, 2006 and JCO, 2013, and JCO, 2014)?
Anaplastic Oligoastrocytoma (AOA), and Anaplastic Oligodendroglioma (AO) s/p surgery<div><br></br></div><div>n=289</div>
What was the regimen studied in RTOG 9402 Cairncross et al (JCO, 2006 and JCO, 2013, and JCO, 2014)?
“<b>→</b><i>neoadj </i><i>dose escalated PCV x4</i> (procarbaine, CCNU, vincristine) → RT 59.4 Gy<br></br>vs. <br></br>→RT 59.4 Gy”
What were the results of RTOG 9402 Cairncross et al (JCO, 2006 and JCO, 2013, and JCO, 2014)?
“<img></img>”
What was the patient population studied in van den Bent, EORTC 26951 (JCO 2006)
Anaplastic Oligoastrocytoma (AOA), and Anaplastic Oligodendroglioma (AO) s/p surgery<div><br></br></div><div>n=368</div>
What was the regimen studied in van den Bent, EORTC 26951 (JCO 2006)?
“→RT 59.4 Gy → <i>adj</i> <span>PCV</span> x6 <br></br>vs. <br></br>→RT alone (PCV allowed at progression)”
What were the results of van den Bent, EORTC 26951 (JCO 2006)?
“<img></img><div><img></img><br></br><div><br></br></div></div>”
What trial demonstrated improvement in PFS but not OS in AO with <i><b>adjuvant </b></i>PCV?
EORTC 26951 van den Bent et al, JCO, 2006 and JCO, 2013<div><br></br></div><div><i>RTOG 9402 was neoadjuvant PCV</i></div>
What was the patient population studied in NOA-04 Wick et al (JCO, 2009;Neuro Oncol 2016)?
“AA (some AO, AOA), KPS≥70<div><br></br></div><div>n=274<br></br><br></br>["”AOA”” diagnosis is now strongly discouraged in WHO 2016]</div>”
What was the regimen studied in NOA-04 Wick et al (JCO, 2009;Neuro Oncol 2016)?
→60 Gy (Arm A) <br></br>vs. <br></br>→PCV/TMZ (Arm B1/B2)<br></br><br></br>Crossover at toxicity or progression: <br></br>•Arm A→PCV or tem<br></br>•Arm B→RT<br></br><br></br>Primary endpoint: TTF
What were the results of NOA-04 Wick et al (JCO, 2009;Neuro Oncol 2016)?
“•Median TTF, PFS, and OS were similar for arms A and B1/2<div><br></br><span>•IDH1 mutation is strongest prognostic factor, even more than 1p19q codel</span><br></br>•methylated-MGMT and oligo histology also associated with better PFS (methylated-MGMT gave same prognosis with chemo and RT)</div>”
What trial demonstrated no change in outcomes in AA and AO sequencing order of RT and chemo?
NOA-04 Wick et al (JCO, 2009;Neuro Oncol 2016)<div><br></br></div><div>Molecular diagnosis is superior to histology to convey prognosis.<br></br></div><div><br></br>No differential activity of chemo vs. RT in any subgroup.<br></br></div>
What was the patient polutation studied inCATNON (van den Bent et al, ASCO, 2019)?
“<span>anaplastic glioma</span> <span>without</span> 1p19q co-deletion”
What was the regimen studied in CATNON (van den Bent et al, ASCO, 2019)?
“→RT alone 59.4 Gy<br></br>vs. <br></br>→RT with conc TMZ <br></br>vs. <br></br><span>→RT with adj TMZ</span> <br></br>vs. <br></br>→RT with conc & adj TMZ”
What were the results of CATNON (van den Bent et al, ASCO, 2019)?
○ Interim results for arms ± adjuvant TMZ: 5y OS 44→ 56%, MPFS 19→ 43 mo. IDHmt benefit from adjuvant TMZ.<div><br></br>○ ASCO results for ± concurrent TMZ: HR 0.97. 5y OS ~50%. Trend to benefit with concurrent TMZ for IDHmt.</div>
What trial demonstrated the following:<div>-OS benefit with adj TMZ in IDH mutant tumors but not IDH wt. <br></br>-No benefit to conc TMZ, but there is a trend to benefit with the addition of conc to adj in IDH mutant?<br></br></div>
CATNON (van den Bent et al, ASCO, 2019)
What is the patient population and regimen in the ongoingCODEL (Jaeckle et al, Neuro Oncol. 2020)?
grade IIIwith 1p19qcodel glioma and grade II oligo with age≥40 or subtotal resection<div><br></br></div><div><br></br>→TMZ alone<br></br></div><div>vs.<br></br>→RT 59.4 Gy then PCV<br></br>vs.<br></br>→RT + conc and adj TMZ</div>
<div>What was the patient population studied in RTOG 9802 Shaw et al (JCO, 2012, Buckner et al, NEJM, 2016</div>
Bell et al, JCO, 2020)?
WHO Grade II astrocytoma, oligoastrocytoma, or oligodendroglioma<div><br></br></div><div>n=365</div>
What was the regimen studied in RTOG 9802 Shaw et al (JCO, 2012, Buckner et al, NEJM, 2016<br></br>Bell et al, JCO, 2020)?
“High risk (age ≥40 or STR):<br></br> <br></br>→<span>54 Gy RT → PCV x6</span><br></br>vs. <br></br><span>→</span>54 Gy RT <br></br><br></br>Low risk: obs<span><br></br></span><br></br>PCV= procarbazine/CCNU/vincristine”
What were the results of RTOG 9802 Shaw et al (JCO, 2012, Buckner et al, NEJM, 2016<br></br>Bell et al, JCO, 2020)?
“PFS and OS improved with PCV<br></br><span>Median OS 13.3 yrs vs. 7.8 <br></br>Median PFS 10.4 yrs vs. 4.0</span><div><br></br>•On subanalysis, benefit only in IDH-mutant (non-codeleted or codeleted). There is no benefit to chemo in IDH-wt</div>”
What trial demonstrated an improvement in OS and PFS in high risk low grade glioma with the addition of PCV to radiation?<br></br>
RTOG 9802 Shaw et al (JCO, 2012, Buckner et al, NEJM, 2016, Bell et al, JCO, 2020)<div><br></br>On subanalysis, benefit only in IDH-mutant (non-codeleted or codeleted). There is no benefit to chemo in IDH-wt</div>
What was the patient population in INT/NCCTG 86-72-51(Shaw et al, JCO, 2002<br></br>Breen et al, Neuro Oncol, 2020)?
WHO I-II disease s/p surgery<div><br></br></div><div>n=203</div>
What was the regimen studied in INT/NCCTG 86-72-51(Shaw et al, JCO, 2002, Breen et al, Neuro Oncol, 2020)?
“<span>→50.4 Gy</span> <br></br>vs. <br></br>→64.8 Gy”
What were the results of INT/NCCTG 86-72-51(Shaw et al, JCO, 2002,Breen et al, Neuro Oncol, 2020)?
No difference in OS or PFS <br></br>5-yr OS 72% low dose vs. 64% <br></br><br></br>•More Grade 3-5 toxicity with high dose. <br></br>•Favorable prognostic factors: age <40, oligo histo
<div>What trial demonstrated no OS benefit to dose escalation (50.4 vs 64.8 Gy) in low grade glioma (necrosis is increased) ?</div>
INT/NCCTG 86-72-51(Shaw et al, JCO, 2002,Breen et al, Neuro Oncol, 2020)
What was the patient population studied in Believers trial EORTC 22844?
WHO I-II disease s/p surgery<div><br></br></div><div>n=343</div>
What was the regimen studied in Believers trial EORTC 22844?
<div>→45 Gy <br></br>vs. <br></br>→59.4 Gy<br></br></div>
<div><br></br></div>
<div><br></br></div>
low-grade astrocytomas, oligodendrogliomas, and mixed oligoastrocyatoma,<br></br>ages 16 to 65, KPS ≥60, randomized to 45 Gy/25 fx versus 59.4 Gy/33 fx after<br></br>surgery (any degree of resection).
What were the results of Believers trial EORTC 22844?
“No difference in 5-yr OS (59% vs. 58%) or PFS (50% vs. 47%) with dose escalation (45Gy vs 59.4)<div><br></br></div><div><br></br><span>Prognostic variables: size ≥6 cm, age ≥40, tumor crossing midline, astrocytoma, neuro deficits [mnemonic: ““SATAN”” criteria]<br></br>3-5 factors is high risk</span></div>”
What trial demonstrated no role for dose escalation (45Gy vs 59.4Gy) in WHO GII (although molecular information is not available on this trial)?
Believers trial EORTC 22844<div><br></br>Pignatti risk factors (SATAN) : preop S ize ≥ 6 cm, A ge ≥ 40y, bihemispherical T umor, A A, or a pre op N euro fxn status >1.</div>
What was the patient population studied in Nonbelievers trial EORTC 22845?
WHO I-II s/p surgery (any kind)<div><br></br></div><div>n=311</div>
What was the regimen studied Nonbelievers trial EORTC 22845?
“<span>→54 Gy</span>/ 30 fx<br></br>vs. <br></br>→obs (RT allowed at recurrence)”
What were the results of Nonbelievers trialEORTC 22845?
“5-yr PFS improved RT 55% vs. 35%<br></br>5-yr OS unchanged at 66-68%<div><br></br><span>•Rate of malignant transformation 72% vs. 66% (NS)</span><br></br>•No changes in cognitive deficits after treatment<br></br>•RT helped to control seizures</div>”
What trial demonstated immediate(vs. delayed) RT improved PFS and decreased seizure rate, but did not improve OS?
Nonbelievers trialEORTC 22845<div><br></br></div><div>Note that 65% of pts in observation arm eventually received RT salvage contributing to higher than expected surival.</div>
What was the patient population studied in Baumert, EORTC 22033-26033 (Lancet Oncol 2016)?
<div>LGG with≥1 high-risk feature (Age ≥40, progressive mass, new or worsening neuro symptoms, intractable seizures)</div>
<div><br></br></div>
<div>n=477</div>
What was the regimen studied inBaumert, EORTC 22033-26033 (Lancet Oncol 2016)?
→50.4 Gy <br></br>vs. <br></br>→dose dense TMZ (75 mg/m2 days 1–21 of a 28-day cycle, max 12 cycles)
What were the results of Baumert, EORTC 22033-26033 (Lancet Oncol 2016)?
PFS 46 mos with RT vs. 39 mos TMZ, p=0.22<div><br></br>•If IDHmt/non-codel, RT had longer PFS. No different in PFS with IDHmt/codel and IDHwt tumors<br></br>•Median OS not reached<br></br>•No differences in HRQOL or global cognitive function between groups</div>
What trial demonstrated no significant difference in PFS for LGG treated withRT alone versus TMZ alone?
Baumert, EORTC 22033-26033 (Lancet Oncol 2016)<div><br></br></div><div>Criteria used in this study are similar to the so called SATAN criteria from the EORTC Believers’ study but modified (Karim 1996).<br></br></div>
What was the patient population studied in Fisher, RTOG 0424 (IJROBP 2015)?
Low grade glioma (high risk) with ≥3 risk factors (age ≥40, astrocytoma, crosses midline, size 6 cm, pre-op neuro function status >1)<div><br></br></div><div>n=129</div>
What was the regimen studied in Fisher, RTOG 0424 (IJROBP 2015)?
Phase II<br></br>54 Gy + conc and adj TMZ
What were the results of Fisher, RTOG 0424 (IJROBP 2015)?
“<span>3-yr OS 74% [improved from historical control 54%]</span><br></br><br></br>Median OS 8.2 yrs<br></br>Median PFS 4.5 yrs <br></br>MGMT associated with improved OS<br></br><br></br>”
What trial demonstrated improved OS in high risk LGG compared to historical controls treated with RT + TMZ?
Fisher, RTOG 0424 (IJROBP 2015)
What was the patient population studied in RTOG 0539?
Meningioma<div>Low risk: Grade I GTR and STR<br></br>Int risk: Grade I recurrent or grade II GTR<br></br>High risk: Grade II recurrent or STR, or grade III any<br></br></div><div><br></br></div><div>n= 244</div>
<div>What was the regimen studied in RTOG 0539?<br></br></div>
“Phase II<br></br>•<span>Low risk (</span>G1, GTR/STR): obs<br></br>•<span>Int risk (</span>G1 recur, G2 GTR): 54 Gy (with CTV 1.0 cm, 0.5 cm CTV at barriers)<br></br>•<span>High risk (</span>G2 recur/STR, G3 STR): 54 Gy (2.0 cm CTV) and 60 Gy (1.0 cm CTV)<br></br><br></br>Edema and dural tail are not included in volumes”
What were the results of RTOG 0539?
“<img></img><br></br><br></br>”
What trial supports observation for low-risk pts with meningioma and 54 Gy for intermediate risk pts WHOgrade I pts s/p STR may warrant adjuvant RT (crude failure rate 40%)?
RTO 0539
What trial randomized unruptured AVMs to medical management +/- intervention (SRS, embolization, neurosurgery or combination)?
ARUBA (2020)<div>Unruptured AVM<br></br><br></br>(Characteristics: Spetzler-Martin grade I-III in ~30% each, and grade IV in ~10%)<br></br></div>
What were the results of the ARUBA trial randomizing unruptured AVMs to medical management +/- intervention (SRS, embolization, neurosurgery or combination)?
-Mean f/u of 50 mos<br></br>-Death or stroke 3.39 (medical mngmt) vs. 12.32 per 100 pt-years<br></br>-Adverse events 59% vs. 79%<br></br>
What trial demonstrated less death, stroke, and adverse effects with medical management alone compared to interventional therapy (SRS, surgery, or embolization) in unruptured AVM?
ARUBA
Which systematic review outlined outcomes of SRS for trigeminal neuralgia?
“International Stereotactic Radiosurgery Society<div><span><a>Tuleasca et al, J Neurosurg, 2020</a></span></div><div>65 studies, 6461 patients<i><u><br></br></u></i><div><br></br></div></div>”
What were the results of the International Stereotactic Radiosurgery Society Trigeminal Neuralgia Systematic Review?
-Mean freedom from pain 80-87%<br></br>-(no difference in GK, LINAC, or CK)<br></br>-Mean time to relief 15-81 days<br></br>-Hypoesthesia ranges 0-17%<br></br>-Mean recurrence 25-32%<br></br>-(For recurrence, LINAC was better than GK. No difference between GK and CK)<br></br>7-yr pain relief 22-60%<br></br>10-yr pain relief 30-45%
What were the results of the Acoustic Neuroma prospective review out of Timone Hospital Marseille (France) comparing surgery vs GKS?
“n=207<div>surgery vs. GKS<br></br>•CN VII disturbance: 37% vs. 0%<br></br>•V disturbancs: 29% vs. 4%<br></br><span>•Hearing preserved: 37.5% vs. 70%</span><br></br>•Hospital stay: 23 days vs. 3 days<br></br></div>”
“What were the results of the results Acoustic Neuroma retrospective reviewout of Thomas Jefferson (<span><a>Andrews et al, IJROBP, 2001</a>)</span><span></span>comparing SRS (12Gy) vs FSRT (50 Gy/ 25fx)?”
SRS v FSRT<div>•Tumor control 98% SRS vs. 97% FSRT<br></br>•CNV preservation 95% vs. 93%<br></br>•CNVII preservation 98% vs. 98%<br></br>•Hearing preservation 33% vs. 81%<br></br></div>
What were the results of the COMS (2006) uveal melanoma trial comparing outcome between plaque brachytherapy and enucleation?
“n=1317<div>Uveal melanoma, selected T2 tumors (<span>medium</span>)<br></br></div><div><br></br></div><div>•12-yr all-cause mortality 41-43%, not different<br></br>•LF <10%<br></br>•But, 3-yr blindness 43%<br></br></div>”
