* Minesh Mehta, Northwestern University Chicago, IL
Consultant: Adnexus, Bayer, Merck, Tomotherapy Stock Options: Colby, Pharmacyclics, Procertus, Stemina, Tomotherapy Board of Directors: Pharmacyclics Data Safety Monitoring Boards: Apogenix Medical Advisory Boards: Colby, Stemina, Procertus Speaker: Merck IP/Patents:Procertus *
*Discuss the role of whole brain radiotherapy in preventing the development of brain metastases in small-cell and non-small cell lung cancer *Discuss the role of radiosurgery in managing brain metastases from NSCLC *Discuss the role of WBRT in conjunction with surgery or SRS *
*Although SCLC responds dramatically to chemotherapy, it does not readily penetrate the BBB, resulting in a microscopic sanctuary site. *Intracranial failure rates therefore remain very high *Because of the innate sensitivity of SCLC to XRT, low dose cranial treatment should reduce the likelihood of developing brain mets *Several clinical trials have validated this and a large 1999 meta-analysis showed that PCI reduces the 3-year rate of brain mets by 25% and improves survival by 5% *
First-Line Chemo-RX: Response of Asymptomatic Brain Metastases From Small-Cell Lung Cancer to Systemic First-Line Chemotherapy* CNS Response Rate: 27% Systemic Response Rate : 73% *Cyt, Adria, & VP16 Tatjana et al., J. Clin Oncol vol 24, pp2079-2083, 2006
n Meta-Analysis of Prophylactic 7 randomized trials, 987 pts with CR; almost all had LS Dz Cranial Irradiation Auperin et al, NEJM, 1999 Death Brain Mets n 5% increase in survival at 3 yrs n Higher dose improved local recurrence but no effect on survival 16% risk 54% risk
PCI in ES-SCLC - Study Design Slotman B et al NEJM: 2007 Chemotherapy (4-6 cycles) No response Any response R PCI 20-30 Gy in 5-12 fractions < 5 weeks 4-6 weeks Stratification: - Institute - Performance score No PCI Primary endpoint reduction in risk of symptomatic brain mets (HR=0.44)
Symptomatic brain metastases Months from moment of randomization
Slotman JCO, 2009 Hair Loss Global Health Status Fatigue Role Functioning Cognitive Functioning Months from moment of randomization Emotional Functioning
Summary: PCI in ES-SCLC PCI significantly reduces the risk of symptomatic brain metastases (p<0.001; HR=0.27; 14.6 vs. 40.4% at 1 yr) No difference in time to extra-cranial progression PCI significantly prolongs failure-free survival and overall survival (Overall survival: p=0.003; HR=0.68; 27.1 vs. 13.3% at 1 yr) PCI is well tolerated and does not substantially influence global QoL/health status/cognitive function
* RTOG 0214
No progression after curative therapy for Stage IIIA/B NSCLC* S T R A T I F Y Stage 1. IIIA 2. IIIB Histology 1. SCCa 2. Non-SCCa Treatment 1. Surgery 2. No Surgery R A N D O M I Z E PCI 30Gy at 2Gy/Fx OBSERVATION *No CNS metastases by brain MRI or CT *
Accrual: Sept. 19, 2001 Aug 30, 2007 Early closure due to slow accrual Targeted Accrual 1058 Actual 356 Ineligible 9 Withdrew Consent 7 Evaluable 340 All patients potentially followed a minimum of 12 months *
PCI Observation 1 yr OS 75.6% 76.9% p=0.86 MS (mos) 25.8 24.8 *
Disease-Free Survival (%) 100 / / / / / 75 / 50 25 PCI Observation 1 yr DFS 56.4% 51.2% p=0.11 / //// // PCI Control Fail 108 132 Total 163 177 p= 0.11 HR= 1.23 (0.95, 1.59) 0 0 3 6 9 12 Patients at Risk Months since Randomization PCI 163 147 119 101 86 Control 177 158 121 103 86 *
CNS Mets Failure (%) 100 75 PCI Control Fail 15 36 Total 163 p= 0.004 177 HR=2.35 (1.29, 4.30) 50 25 PCI Control CNS Mets 7.7% 18.0% p=0.004 0 Patients at Risk PCI Control 0 3 6 9 12 Months since Randomization 163 177 156 165 145 144 128 129 109 113 *
MMSE Score * 30 20 10 0-10 Baseline Month 3 Month 6 Time Point Month 12 PCI Raw Score PCI Change Score
* 25 20 15 10 5 0-5 Baseline Month 3 Month 6 Month 12 PCI Raw Score PCI Change Score
All PCI NSCLC Trials Show Benefit CNS Failures Study N No PCI PCI p value VALG, JAMA 1981 281 13% 6% 0.04 MDACC, J Neuro-Onc 1984 97 27% 4% 0.002 RTOG 8403, IJROBP 1991 187 19% 9% 0.1 Pottgenet.al, JCO 2007 112 24% 9% 0.02 Movsas et.al, ASTRO 2009 340 18% 8% 0.004 Cumulative Experience 1017 13-27% 4-9% Prospective Randomized Trials of PCI in NSCLC
* *NCF deterioration occurs early and often. *We have analyzed the time course of NCF decline employing 8 prospectively measured domains in 208 brain metastases patients treated with 30 Gy WBRT and have found that: *Median time to NCF deterioration was longer in good than in poor responders. *Memory was most susceptible to early decline, even in patients with non-progressing brain metastases: the role of the hippocampus
*Limit PCI to very high risk populations only *Non-squamous NSCLC patients have 27% risk *Neuroprotectors *RTOG 0614, Memantine *Use BBB-penetrating chemotherapy, e.g. TMZ *SP PO5416, randomized phase II trial *Hippocampal avoidance *To protect the radiosensitive neuro-progenitor stem cell compartment (not anatomic protection) *
* Definitive WBRT Alone
* Class I <65 (age) KPS >70 Controlled primary No extracranial mets Class II all others Class III KPS <70 Median Survival 7.1 months 4.2 months 2.3 months % in Class 20 65 15 All brain metastases are not equal. Gaspar L, et al. Int J Radiat Oncol Biol Phys. 2000;47:1001-1006. Gaspar L, et al. Int J Radiat Oncol Biol Phys. 1997;37:745-751.
* Tumor N (%) Age 60 KPS 70 Mets >3 EC Mets NSCLC 1888 (44) 57 % 85 % 24 % 33 % Breast 642 (15) 29 % 89 % 36 % 48 % Melanoma 483 (11) 40 % 92 % 30 % 67 % Total 4259 (100) 50 % 85 % 27 % 41 % Sperduto, et al, ASTRO 2010
* Tumor MS GPA 0-1 GPA 1.5-2.5 GPA 3 GPA 3.5-4 NSCLC 7 3 6.5 11.3 14.8 <.0001 Breast 12 6 9.4 16.9 18.7 <.0001 Melanoma 6.7 3.4 4.7 8.8 13.2 <.0001 p Sperduto, et al, ASTRO 2010
*
WBRT + MGd Response Analysis 135 pts at 2 mo Volume reduction > 45% Good responders Poor responders Volume reduction < 45%
Tumor Shrinkage Prolonged Survival Response MS Good 300+26 d Poor 240+19 d P-value 0.03
* PEGND Test
*
% Alive * 100 80 60 40 20 RT + RS (MS=6.5 mos) RT alone (MS=4.9 mos) P=0.0470 0 0 6 12 18 24 Months Andrews DW, et al. Lancet 2004;363:1665-1672.
* Study WBRT + SRS P value When RTOG 71% 82%.01 1yr Tufts 87% 91% NS? Pittsburgh 8% 100%.0005 1 yr
* *Bhatnagar et al., IJROBP, 2006. *Retrospective study: *205 patients with various malignancies *Radiosurgery for 4 or more metastases. *Median marginal dose of 16 Gy. *Median overall survival was 8 months. * RPA classes I, II, and III: 18, 9, and 3 months *Tumor volume was the most significant predictor of survival and the only significant predictor of local control; number of lesions was not a significant prognostic factor.
*
*Very High Brain Relapse After Surgery if WBRT is Omitted Complete resection without WBRT leads to 70% actuarial relapse This is a relative risk of 3 Patchell, JAMA.1998:280:1485
* Author, Year Patchell, 1998 Aoyama, 2006 Chang, 2010 Kocher, 2010 Kocher, 2010 Local therapy No WBRT Any brain failure No WBRT Local brain failure No WBRT Distant brain failure WBRT WBRT WBRT Any brain failure Local brain failure Distant brain failure S 70% 68% 50% 24% 21% 18% SRS 76% 27% 64% 47% 11% 42% SRS 73% 33% 55% 27% 0% 27% S 59% 42% 27% 23% SRS or S 78% 42% Range 70-78% 27-69% 42-64% 24-47% 0-27% 18-42%
* 82 pts on JROSG 99-1 had MMSE 27 Median time to 3 point drop: 16.5 vs. 7.6 months, in favor of WBRT+SRS (p =.05) 12 and 24 month freedom from 3 point drop: 76 and 69% for WBRT+SRS vs. 59 and 52% for SRS alone Progressive disease is worse than WBRT Aoyama, Int J Radiat Oncol Biol Phys, 68:1388-395, 2007
MDACCC Trial: Neurocognitive Decline by HVLT Mean Probability of NCF Decline SRS 23% SRS+WBRT 49%
Roles of WBRT for NSCLC Brain Mets Preventative SCLC NSCLC Therapeutic Multiple Brain Mets Adjunctive To reduce local failure after SRS/S To reduce regional failure after SRS/S Toxicities MMSE changes are minor to none and might even improve Finer tools pick up some decline, mostly early, with some late recovery *