3DisclosuresI have given an awful lot of whole brain radiation therapy in my careerI am bald (Rogaine did not help)I am a Toronto Maple Leafs fan
4Presentation Outline I What is Oligometastatic Disease?Prognostic Factors: From RPA to GPAWBRT and SRS: Current PerspectivesNeurocognitive Impairment from RTHippocampal Avoidance(HA)IMRT for WBRT and SIB of MetastasesExample CaseConclusionsDepartment ofRadiation Oncology
5What is Oligometastatic Disease? I’m not sure...Oligo means “a few”RTOG and EORTC enrolled patients with 1-3 metsJROSG-99-1 enrolled 1-4 metsPMH “oligo brain mets clinic” accepts patients with up to 6 mets
6What is Oligometastatic Disease? Should we think about total volume of intracranial mets as well as the # of mets?SRS alone for “oligomets” and delay WBRT?
8What is Oligometastatic Disease? Should we think about the total volume of intracranial metastases?M.Follwell/PMH presentation at CARO 2011: Baseline Cumulative Volume >6.0 cc predictive for decreased O.S.I am still confused about “oligometastatic” disease….RCT have included 1-4 mets
9RTOG RPA Classification Gaspar et al,IJROBP 1997 Vol. 37: 745-741
11Brain Mets DS GPA Sperduto et al IJROBP Vol.77,No.3 pp.655-61,2010 Disease specific and includes patients treated with S, SRS and WBRTFar more complicated than traditional RTOG RPAGPA score out of 4 makes sense in USA
12Brain Mets GPA Sperduto et al IJROBP Vol.77,No.3 pp.655-61,2010 Prognostic index based on 4,259 patientsRetrospectiveS,SRS,WBRTDisease specific
13Brain Mets GPA Sperduto et al IJROBP Vol.77,No.3 pp.655-61,2010
14Brain Mets GPA Sperduto et al IJROBP Vol.77,No.3 pp.655-61,2010
15Brain Metastases: Current Perspectives WBRT improves CNS disease control i.e. micrometastases in the rest of the brainWBRT results in significant neurocognitive impairmentWBRT does not improve overall survival
16Brain Metastases: Current Perspectives What are some of the endpoints to be considered when assessing RT (WBRT or SRS) for brain metastases?Local Control of existing metsCNS Control (mets and “micro-mets”)Overall Survival
17Brain Metastases: Current Perspectives What are some of the endpoints to be considered when assessing RT (WBRT or SRS) for brain metastases?Quality of LifeFunctional IndependenceNeurocognitive FunctionSteroid Requirements
18Brain Metastases: Current Perspectives What other aspects should be considered when assessing RT (WBRT or SRS) for brain metastases?$$$$Availability and timely access to RTHow much RT, how often to deliver RT in patients with limited life expectancy?
19Brain Metastases: Current Perspectives Which are the most important endpoints when assessing whole brain radiation therapy?Remember that the treatment intent is palliative ....
21EORTC 22952-26001 Kocher et al, JCO 29:134-141, 2011 Adjuvant WBRT vs. Observation after SRS or S in Patients with 1-3 Cerebral Metastases359 patients accrued
22EORTC 22952-26001 SRS in 199, S in 160 53% NSCLC S arm: 95% had single mets; larger lesions vs. SRS and more often in post. fossaWBRT 30 Gy/10 fr.SRS 20 Gy peripheral dose, maximum lesion diameter 35 mmPatient groups well balanced
27EORTCWBRT in patients with 1-3 mets does not prolong overall survival or survival with functional independence after S or SRSWBRT reduces local progression, intracranial progression and improves PFSAfter S alone local progression rate is 59% at 2 years
28EORTCGreater incidence of serious adverse events in WBRT arm(13 vs. 3 SAE)Results very similar to Patchell (S) and JROSG-99-1 (SRS) trialsReasonable to delay WBRT in patients with limited # metsLocal therapy (e.g SRS) to surgical bed after resection?
29Neurocognition and WBRT Neurocognition in Patients Treated with SRS or SRS plus WBRT: A Randomized Controlled TrialChang et al Lancet Oncol :58 patients randomizedPrimary endpoint: HVLT-R at 4 monthsWBRT 30 Gy/12 fractions
30Neurocognition and WBRT Trial closed early (58 patients)Significant difference in total recall at 4 months, SRS and WBRT inferior to SRSChang et al Lancet Oncol :
31Does WBRT Adversely Effect Overall Survival. Chang et al Lancet Oncol Inferior survival in SRS+WBRT armPatients in SRS arm received more chemo and started earlierSalvage surgery more common in SRS arm
32Does WBRT Adversely Effect Overall Survival Does WBRT Adversely Effect Overall Survival? Aoyama et al, JAMA 2006; 295:No adverse effect in JROSG-99-1)132 patients, accrual , 1-4 metsmedian survival 7.5 months WBRT + SRS vs. 8.0 months SRS
33Does WBRT Adversely Effect Overall Survival? Negative effect in Chang trial not seen in JROSG-99-1, EORTC (reviewed earlier) and a surgical trial published by PatchellNo survival benefit as an “adjuvant” therapy
35Hippocampal Avoidance Emerging evidence suggests that a neural stem cell compartment in the hippocampus is key to the pathogenesis of neurocognitive deficits observed after cranial RTNeural progenitor cells are anatomically clustered within the dentate gyrus of the hippocampus
37Hippocampal Avoidance Following RT neural progenitor cells become less proliferative, more apoptotic, more likely to adopt a gliogenic fateInflammation in the area surrounding the neural stem cells is a major contributing factor to RT effect
38Hippocampal Avoidance Hippocampus + 5 mm= Hippocampal Avoidance RegionPlanning study by Gondi et al (5 patients) showed mean HAR of 3.3 cubic cmHAR represents approx. 2% of whole brain volume
39Hippocampal Avoidance Gondi et al, Radiother. Oncol Hippocampal Avoidance Gondi et al, Radiother. Oncol. 95: % mets occur outside HAR
40Hippocampal Avoidance HA-WBRT technique (Gondi et al)
41Hippocampal Avoidance Save the hippos!HA-WBRT may prevent/reduce neurocognitive impairmentRTOG 0933 is evaluating HA-WBRT and NCFHA-WBRT should only be done within clinical trials at this time
42WBRT and SIB SIB=simultaneous integrated boost of metastases Tomotherapy or VMAT are efficient ways of delivering SIB with WBRTUWO (Rodrigues et al) performed an elegant Phase I clinical to assess safety of this approach using helical tomotherapy
43WBRT and SIB Phase I Trial 48 patients, 70 mets WBRT 30 Gy/10 fr. with SIB 5-30 Gy in 5 Gy incrementsWell tolerated, no dose limiting toxicities even at 60 Gy/10 fr.Median O.S monthsRodrigues et al, IJROBP Vol.80, No.4, pp , 2011
44WBRT and SIB Rodrigues et al, IJROBP Vol.80, No.4, pp. 1128-1133, 2011
45WBRT and SIB Rodrigues et al, IJROBP Vol.80, No.4, pp. 1128-1133, 2011
46WBRT with SIB and HA It can be done if you let Fred do it! Planning study at BCCA10 patients,18 metsSIB mets GyWBRT Gy/15 frMean hippocampal dose 5.23 Gy-2Hsu et al, IJROBP 2009
4963 y. o. woman. Originally diagnosed with breast cancer 7 years ago 63 y.o. woman. Originally diagnosed with breast cancer 7 years ago. Left mastectomy. In 2007 had right hip fracture – hip replacement and XRT (Dr. Rutledge). Recently feels “off balance”. Presents with left homonymous hemianopsia, headache and vomitting.
50Example Case Various options... 63 year old female,metastatic breast cancer,excellent conditionRTOG RPA class 2GPA 3 or 4, median survival months6 mets, largest/symptomatic met excised
52ConclusionsVarious management options should be considered and treatment should be individualizedWBRT should not be abandoned but must evolve/improveHA-WBRT and SIB should be studied- in clinical trials that Atlantic Canadians can participate in