Cécile Le Péchoux Department of Radiation Oncology, Institut Gustave Roussy, Villejuif France Amsterdam 2010

Prophylactic Cranial Irradiation in Lung Cancer Cécile Le Péchoux Department of Radiation Oncology, Institut Gustave Roussy, Villejuif France Amsterdam 2010 Prophylactic cranial irradiation PCI was introduced in the early seventies Retrospective studies showed it decreased the rate of brain metastases Then several randomized studies were carried on, in the 70-80s vlung cancer in the earlier studies vsmall cell lung cancer ++

Small Cell Lung cancer Less frequent Much more dat on PCI Before PCIO PCI to all patients? With PCI, significant reduction in the risk of brain metastasis (about 50%) vincidence of BM 22% vs 6% in old trials vincidence of BM 50% vs 25% in new trials (CR) PCI as part of standard ttt : a controversial issue v No prolongation of survival in individual trials v Possible neurotoxic effects of irradiation as reported in retrospective studies

Toxicity related to PCI Acute toxicity : Headache Nausea Fatigue Concentration difficulties Alopecia Late toxicity Memory deficiency Ideation deficiency Neuro-cognitive deficit Ataxia, Epilepsy, Dementia rare Abnomalities on CT or MRI frequent: affecting white matter PCI neurotoxicity Possible confounding factors v Treatment-related Total dose Dose per fraction (> 3 Gy) Concomitant chemotherapy (MTX, Nitroso-urea) v Patient and/or tumour related Long-term tobacco use Age > 60 Paraneoplastic syndromes, micrometastases Depression

Controversy over PCI Neurotoxicity Neurotoxicity reported in retrospective studies++ Importance of baseline evaluations v Abnormal in 60% of pts (Gregor et al) v Abnormal in 40% of pts (Arriagada et al) No significant neurological deterioration in 2 large randomised trials among PCI patients in the available follow-up of 2 years (Arriagada et al, Gregor et al) Controversy over PCI Survival The Prophylactic Cranial Irradiation Overview Collaborative Group undertook a Meta-analysis to determine whether PCI might lead to a moderate improvement in survival: v 7 trials (987 patients with SCLC in CR) R No PCI (461 pts) PCI (526 pts): Doses 8 Gy/1 fr to 40 Gy/20 fr

PCI prevents the emergence of BMets and not simply delays them! 1,00 0,90 0,80 0,70 0,60 0,50 0,40 0,30 0,20 0,10 0,00 3yrs rate of BM 58.6% versus 33.3% in the PCI group (p<0.001) 0 12 24 36 48 60 72 84 96 Months since randomization No PCI PCI At risk 457 171 88 57 41 32 21 18 14 1 524 248 133 96 66 52 40 29 17 21 Overall Survival 3 yrs OS: 15.3% versus 20.7% in the PCI group At risk 1,00 0,90 0,80 0,70 0,60 0,50 0,40 0,30 0,20 0,10 0,00 (p=0.01) No PCI PCI 0 12 24 36 48 60 72 84 96 Months since randomization 461 224 103 61 44 34 23 19 15 526 276 139 101 66 52 40 29 17

PCIO What about extensive disease? About 15% of patients included in the meta-analysis had extensive disease PCI improved survival even in this subgroup of patients A specific EORTC trial has adressed this issue EORTC randomized study PCI in ED SCLC Chemotherapy (4-6 cycles) No response Any response Random PCI 20-30 Gy in 5-12 fractions < 5 weeks Observation 4-6 weeks Stratification: WHO and Institute Slotman et al, NEJM 2007

100 90 80 70 60 50 40 30 20 10 0 Symptomatic brain metastases 40.4% 14.6% BM incidence PCI prevents the emergence of BM and not simply delays them! No PCI At 1 year: 0,20 14.6% vs. PCI 40.4% Months since randomization HR: 0.27 (0.16-0.44) p<0.0001 At risk Control No PCI 457 171 88 57 41 32 21 18 14 524 248 133 96 66 52 40 29 17 PCI 0 4 8 12 16 20 24 28 32 36 1,00 0,90 0,80 0,70 0,60 0,50 0,40 0,30 0,10 0,00 3yr-rate 58.6% 3yr-rate 33.3% 0 12 24 36 48 60 72 84 96 Aupérin et al, NEJM 1999;341:476 (months) Slotman et al, NEJM 2007 Overall survival 100 90 80 70 60 50 At 1 year: 27.1% vs. 13.3% HR: 0.68 (0.52-0.88) p=0.003 40 30 20 10 Control PCI 0 0 4 8 12 16 20 24 28 32 36 (months)

PCIO Meta-analysis Unanswered questions for limited disease? voptimal timing Late? Early? voptimal dose Objective of a new trial in LD? Incidence of brain metastases according to PCI dose Nb evts/nb included pts Category PCI No PCI 8 Gy / 1 fr 9/26 7/16 24-25 Gy / 8-12 fr 105/329 172/338 30 Gy / 10 fr 21/118 32/80 Hazard ratio 0.76 0.52 0.34 36-40 Gy / 18-20 fr 8/51 31/59 0.27 Trend for a PCI dose effect Interaction test Trend test p=0.11 p=0.02 0.0 0.5 1.0 1.5 2.0 PCI better No PCI better Hypothesis: To further reduce incidence of BM by increasing PCI dose with minimal and acceptable toxicity Assessment of a possible neurotoxicity mandatory

EORTC 22003-08004 IFCT 99-01 RTOG 0212 Randomized trial of standard dose to a higher dose prophylactic cranial irradiation (PCI) in limited-stage small cell cancer (SCLC) complete responders (CR): Primary endpoint analysis (PCI99-01, IFCT 99-01, EORTC 22003-08004, RTOG 0212) Funding:Institut Gustave Roussy, Association pour la Recherche sur le Cancer 2001 and Programme Hospitalier de Recherche Clinique, 2007 Inclusion criteria 18 Histologically proven limited-stage SCLC Complete response to induction therapy (established on at least a chest X-ray) Brain CT-scan or MRI at <1 month pre-randomisation Baseline QOL and neurological assessment Age < 70*, WHO performance status < 2 PCI starting as soon as possible after CR Informed consent * except in the US, no age limit

Trial profile Randomization N=720 patients Stratification factors: centre delay between start of induction treatment and rand. ( 90, 91-180, >180 days) age ( 60 yrs, > 60 yrs) 19 Standard dose: 25 Gy 10 fractions/12 days N=360 patients Higher dose: 36 Gy N=360 patients centers optional choice* Conventional RT 18 fractions/24 days (78%) * except in the US, where it is randomized Accelerated hyperfract. RT 24 twice-daily fractions/16 days (22%) Brain metastasis incidence 20 100% 80% 25 Gy 36 Gy 60% At risk 40% 20% 0% 30% 24% 0 1 2 3 4 Years 360 230 103 63 37 360 217 99 53 34 143 brain metastases observed before March 1 st 2007 HR of brain metastasis in 36 Gy versus 25 Gy: 0.77 (0.55-1.08), p=0.13 Le Pechoux et al, Lancet Oncol 09

Overall survival 21 100% 80% 25 Gy 36 Gy Cause of death 25 Gy 36 Gy 60% 40% 20% 37% 42% PCI toxicity 1 1 Thoracic irradiation toxicity 1 3 Chemotherapy toxicity 4 0 Progression 184 216 Other 27 29 At risk 0% 0 1 2 3 4 Years 360 258 114 63 37 360 235 104 58 35 466 deaths observed before March, 1 st 2007 HR of death in 36 Gy versus 25 Gy: 1.22 (1.02-1.47), p=0.03 Le Pechoux et al, Lancet Oncol 09 Neuro-cognitive follow-up among pts with LD SCLC treated with 2 different PCI doses Few patients had severe deterioration of neuropsychological and cognitive functions over 3 years. No significant difference between 25 Gy and 36 Gy arms in terms of QoL and SOMA-LENT evaluation Over time, mild deterioration of certain items such as memory, intellectual deficit and cognitive functions PCI with a total dose of 25 Gy remains the standard of care in limited-stage SCLC.

Conclusion: PCI in SCLC 23 PCI with a total dose of 25 Gy remains the standard of care in limited-stage SCLC. PCI is a standard in patients with extensive disease who respond to treatment Le Pechoux et al, Lancet Oncol 09 Non-Small Cell Lung cancer

PCI or no PCI? in high risk NSCLC patients vin SCLC: very controversial for years, small trials vresults of Meta-analysis: 5% benefit on survival After years, PCI has become A standard for SCLC complete responders v What about PCI in NSCLC?? v As systemic extra-cerebral control has improved, higher rate of BM v Need for a large trial to evaluate PCI in NSCLC PCI - LA-NSCLC CNS Failures Study PCI No PCI PCI VALG 20 Gy (2 Gy X 10) 13% 6% 1981 RTOG 1991 SWOG 1995 CALGB 1992 Stuschke 1999 * 30 Gy (3 Gy X 10) 19% 9% 36 Gy (2 Gy X 18) 16% 8% 30 Gy (2 Gy X 15) 12% 0 30 Gy (2 Gy X 15) 54% 13%

New evidence in favor of PCI in NSCLC? SCHEMA Essen Trial Pottgen et al, JCO 07 ARM A: After mediastinoscopic staging, Stage IIIA operable NSCLC R A N D O M I Z E Control ARM Surg + PORT 50-60 Gy ARM B: 3 cycles CT (EP) HFRT 45Gy and CTcc(EPX2) Surgery AND PCI: 30 Gy 2 Gy/Fraction 15 Daily Fractions 112 patients randomized from Nov 1994 to July 2001 43 pts had PCI Arm A Arm B p 5yr-Risk of BM(1st site) 34.7% 7.8% 0,02 5yr-Risk of BM 27,2% 9,1% 0,04 No difference in neurocognitive deficit

RTOG 0214: A Phase III Comparison of Prophylactic Cranial Irradiation versus Observation in Patients with Locally Advanced Non-Small Cell Lung Cancer Elizabeth Gore, Kyounghwa Bae, Stuart Wong, James Bonner, Alexander Sun, Steven Schild, Laurie Gaspar, Jeffrey Bogart, Maria Werner-Wasik, Wasik, Hak Choy Schema of RTOG 0214 No progression after curative therapy for Stage IIIA/B NSCLC S T R A TI 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 IZ E PCI 30Gy at 2Gy/Fx OBSERVATION 340 pts analysed out of 1058 needed to show a survival improval Primary objective: survival S ary objectives: BM, DFS,QoL, Neuropsychological Function

Conclusion PCI in SCLC is now part of the standard treatment of patients who have had a CR to treatment PCI in NSCLC: insufficient evidence to support the use of PCI in the management of patients with NSCLC treated with curative intent (Conclusion of Cochrane Overview). New trials needed+++ PCI trial in NSCLC NVALT-11/ DLCRG-02 Thank you for your attention!