phase iii randomised trial of conformal versus conventional radiotherapy in young patients with...
TRANSCRIPT
Phase III randomised trial of Conformal versus conventional radiotherapy in young patients with progressive/residual benign/low grade brain tumours
Rakesh JalaliNeuro-Oncology GroupTata Memorial Hospital
Mumbai, INDIA
High-precision radiotherapy for progressive/residual low grade/benign brain tumours
• Physics / dosimetericDose distributions, dose volume histograms, indices
• Clinical Reduction of RT induced toxicity Survival
• Excellent long term control• Advances in technology and increasing use of high precision techniques (Stereotactic RT, IMRT, Proton beam therapy, Tomotherapy, Cyber knife, etc)
Clinical evidence is based on retrospective or relatively few prospective studies
Evaluation of efficacy of modern high-precision RT
Phase III randomized controlled trial
• Age 3-25 years• Residual/progressive low
grade and benign tumours needing RT
• Informed consent• Detailed neurological
endocrine and neuropsychological evaluation
RANDOMIZATION
Stereotactic conformal RT
Conventional RT
Regularevaluations
Stratification • Pre vs. post pubertal• NPS 0-1 vs. 2-3• Hydrocephalus nil/mild vs. moderate/severe
IRB Clearance: May 2001Accrual: 2001 - 2011
SCRT Vs Conventional RT in Children and Young Adults With Low Grade and Benign Brain Tumours
Sponsor: Tata Memorial Hospital
Collaborator: Terry Fox Foundation
Information provided by: Tata Memorial Hospital
ClinicalTrials.gov : NCT00517959
Primary endpointIncidence and magnitude of neuropsychological, cognitive, neuroendocrine and neurological dysfunction in the two armsSecondary endpointSurvival
• Sample size: N=200; 80% power to detect a 15-20% reduction in primary endpoints in SCRT arm compared to conventional RT arm at a significant level of p<0.05• Informed consent (English, Hindi, Marathi)
RT techniques in the two armsHigh precision SCRT Conventional RT
Immobilisation BrainLAB stereotactic mask Thermoplastic mask
Imaging datasets CT + MRI (3D-FSPGR/T2 FLAIR) CT simulation
Volume delineation
CTV= Residual tumour/ tumour bed GTV+3-5mm
CTV=Residual tumour/ tumour bed GTV+3-5mm
Safety margin or Planning target volume (PTV)
2mm; RT delivery under stereotactic guidance
5 mm
Beam planning microMLC based Conformal, non coplanar 6-9 beams
2-3 coplanar beams, appropriate wedges and shielding
Dose/fractionation 54 Gy/ 30 #/ 6 weeks 54 Gy/ 30 #/ 6 weeks
Jalali et al, Radiotherapy and Oncology 2005
Allocated to SCRT arm (n= 105)Received allocated intervention (n=98)
Did not receive (n=7)Consent withdrawn(n=1)Death before RT (n=1)
RT outside study protocol (n=2)Default on RT and death (n=3)
Allocated to Conventional arm (n=95)Received allocated intervention (n=90)
Did not receive(n=5)Consent withdrawn (n=1)Death before RT (n=1)
RT outside study protocol (n=1)Default on RT and death (n=2)
Allocation
Randomised n=200
CONSORT diagram
Evaluation at pre radiotherapy (baseline) followed by serial evaluations post RT - at 6 months and then at 2, 3, 4 and 5 years
Patient demographic profile (n=200)Factor SCRT arm (n=105) Conventional arm (n=95)
Age (in years) Range Median
4-25 years13 years
4-25 years13 years
Sex Male: Female 69:36 63:32
Neurologic performance status 0-1 2-3
7927
7222
Puberty status Pre pubertal Post pubertal
6540
6233
Hydrocephalus Nil/Mild Moderate/severe
7035
6629
Histology Craniopharyngioma Low grade Astrocytoma Optic pathway
Cerebral Cerebellar Ependymomas Others
4020122445
431615165-
IQ patients
Defective <69 16 (17%)
Borderline 70-79 26 (27%)Dull Normal 80-89 21 (22%)
Average 90-109 27 (28%)Bright Normal 110-119 5 (6%)
Superior 120-129 0 (0%)
Very Superior >130 0 (0%)
60% patients at pre RT baseline had below normal values
Jalali et al IJROBP 2006 Jalali et al IJROBP 2010
Time trends in Full scale IQ (FSIQ)
Baseline 06 24 36 48 60
CRT 97 72 61 43 39 29
Conv 83 69 63 51 38 22
IQ VALUES
Follow up in months
Number at risk
p=0.0003 p=0.012
General Linear Model (Hyunh-Feldt test)
Better performance IQ (PQ) in Conformal RT arm
p= 0.055
Memory IQ (MQ) (Age>16 years)
p=0.049
Verbal IQ (VQ) (Age<16 years)
p=0.047
Other cognitive parameters (LOTCA Battery)
Neuro-psychological results : summary
• General Linear Model for repeated measures demonstrated significantly better preservation of FSIQ over time in the high precision Conformal RT (CRT) arm versus Conv RT arm at 3 years (p=0.0003) and at 5 years (p=0.012)
• Significantly better preservation of age adjusted individual domains of verbal quotient VQ (age<16 years) (p=0.047) and memory quotient MQ (age>16 years) (p=0.049) in the CRT compared to Conv RT arm
•Anxiety score between the two arms not significant at 5 years (age<16 years) (p=0.13) and (age>16 years) (p=0.3), but mean depression scores at 5 years in age group <16 years was found to be significant (p=0.01) in favour of CRT arm
• Patients in Conv RT arm had significantly more neurocognitive decline in LOTCA battery at 5 years (p=0.019), particularly in the visuomotor organization and attention concentration domains
Hippocampus and Radiation therapy
• Preclinical models suggest neural stem cell (NSC) compartment may lie in peri-hippocampal subgranular zone (SGZ)
• Modest doses of RT can cause apoptosis and decline in neurogenesis in SGZ in mice
• Clinical data relatively sparse esp for focal RT; WBRT trial encouraging data (RTOG 0933)
• Our earlier data showed significant correlation of RT dose with left temporal lobes (IJROBP 2010)
Monje et al Science 2003Raber et al Radiat Res 2004
Gondi et al IJROBP 2010
Mean dose (Gy) p-value*
FSIQ >10%drop 30.7 0.043
<10% drop 25.4
VQ >10%drop 28.5 0.995
<10% drop 24.6
PQ >10%drop 53.4 0.023
<10% drop 26
Left Hippocampus dose & change in IQ at >3 years follow up
Logistic regression analysis, model fit
Mean doses >30 Gy to hippocampus as a possible dose constraint cut off for IQ decline
Pre RT endocrine evaluation – clinical and biochemical
Definition of endocrine dysfunction at follow up Dysfunction in at least one more new axis compared to previous evaluation
Axis Clinical Biochemical Normal levels
Growth AnthropometryHeight velocity
ITT Peak GHIGF-1 (at 13 years)
>10ng/mlFemale : 126-637ng/ml
Male: 103-603ng/ml
Puberty SMR staging FSHLH
2.5-10mIU/ml2.5-10mIU/ml
Thyroid Clinical evaluation for hypothyroidism
T4 5-12.5mcg/dl
Steroid Clinical evaluation of hypocortisolism
Basal corticolITT
>10mcg/dl>18 mcg/dl
ITT- Insulin tolerance test
Cumulative incidence of new endocrine dysfunction
Patients at risk
6 months 24 months 36 months 48 months 60 months
SCRT 91 66 56 49 33
Conv 82 68 56 46 39
31% SCRT Vs. 51% Conv RTp (one sided) = 0.048
New axis dysfunction in patients with prior dysfunction in at least one axis at baseline
29% SCRT Vs. 52% ConvP = 0.05
Maintained normal endocrine function in all axes
26% SCRT Vs. 15% Conv RTP = 0.05
Comparable overall survival
5 year OSCRT Vs. Conv RT: 90.5% Vs 87.5%
Conclusions• Children and young adults with low grade and benign brain tumours have considerable pre-RT neurocognitive and endocrine dysfunction, especially in tumours located close to Hypothalamic - Pituitary Axis (HPA)
• We demonstrate high level of evidence through this randomised controlled trial that high precision conformal RT is superior to Conventional RT in terms of preservation of neurocognition and significantly less dysfunctions at 5 years follow up.
• This is among the few trials addressing the use of modern conformal RT and generating evidence from an appropriately powered clinical trial with meaningful endpoints.
• Doses to left temporal lobe and left hippocampus appear to correlate significantly with IQ decline, contemporary RT techniques (e.g IMRT, Protons etc) have the potential to achieve these relatively simple constraint models in routine clinical practice
Acknowledgements• Patients and their families• All members of Neuro-Oncology group• Radiation Oncology (Rajiv Sarin, Tejpal Gupta, Debnarayan Dutta, Uday Krishna, Vikas Kothawade)• Clinical Psychology (Savita Goswami, Jyotia Deodhar)• Clinical Endocrinology, KEM (N Shah, P Menon, A Lila)• Neurosurgery (KEM, Bombay Hospital, TMH)• Medical Physics• Trial coordinators • Statistician (Sadhna Kannan)
www.braintumourindia.org
Terry Fox Foundation India Committee
• Premier forum for neuro-oncology in India• 296 members; neurosurgeons, oncologists, pathologists, radiologists, basic scientists, rehab specialists, etc• Regular CME’s and educational programmes in regional groups
• Aim is bring in uniformity of care
• 7th annual conference from 26-29th March, 2015 at Kochi
www.isnocon2015.com (Pediatric Neuro Oncology is one of the two major themes)
• One of tha main aims is to generate quality data by setting up national studies
www.isno.in