Update on Limited Small Cell Lung Cancer Laurie E Gaspar MD, MBA Prof/Chair Radiation Oncology University of Colorado Denver
Objectives - Limited Radiation Dose Radiation Timing Radiation Volume PCI Neurotoxicity Stereotactic Body Radiation Therapy - Extensive RT Oligometastatic
Intergroup Trial 0096 LSCLC 45 Gy QD or BID R a n d o m i z e 417 pts 45 Gy 25 fx 5 wks QD PE PE PE PE 45 Gy 30 fx 3 wks BID PCI PE PE PE PE PE: q 21 days Cisplatin 60 mg/m 2 day 1 Etoposide 120 mg/m 2 d 1,2,3 PCI: 25 Gy (2.5 Gy qd) Turrisi A et al, NEJM 340:265-71, 1999
Thoracic Radiotherapy Gross tumor, bilateral mediastinum, unilateral hilum No supraclavicular radiation Margin of 1 to 1.5 cm No CT simulation required No field reductions Turrisi A et al, NEJM 340:265-71, 1999
Intergroup Trial 0096 LSCLC 45 Gy QD or BID
Intergroup Trial 0096 LSCLC 45 Gy QD or BID 45 Gy QD 45 Gy BID Median survival 19 m 23 m 5-yr survival 16% 26% p=0.04 Local failure 52% 36% p=0.06 Simultaneous local/distant failure 23% 6% p=0.01 Turrisi A et al, NEJM 340:265-71, 1999
Intergroup Trial 0096 LSCLC 45 Gy QD or BID Landmark study but still controversy and questions Dose/fractionation of radiation therapy? Timing of starting radiation? Target to irradiate? Why would local treatment not affect local control but affect distant relapse?
CALGB 30610/ RTOG 0538 Eligibility LSCLC No contralateral hilar or supraclav N ECOG PS 0-2 Stratification ECOG 0 vs. 1-2 Weight loss Gender 3D vs. IMRT Accrual goal 670-712 R A N D O M I Z E Arm A: Standard Cisplatin/Etoposide x 4 + Concurrent 45 Gy BID Arm B: Cisplatin/Etoposide x 4 + Concurrent 61.2 Gy QD/BID Arm C: Cisplatin/Etoposide x 4 + Concurrent 70 Gy QD 190 patients as of July 2011
CONVERT (EORTC/NCIC) Accrual goal 532 Eligibility LSCLC FEV1/KCO limits V20 < 35% Reasonable RT port ECOG PS 0-2 Stratification ECOG PS 0-1 vs 2 Center Na, Alk phos, LDH 242 accrued as of July 2011 R A N D O M I Z E Arm A: Control Cisplatin/Etoposide x 4-6 cycles Concurrent 45 Gy BID 3 wks Arm B: Experimental Cisplatin/Etoposide x 4-6 cycles Concurrent 66 Gy QD 33 fx
Same question but several differences CALGB/RTOG CONVERT Timing of RT Cycle 1 or 2 Cycle 2 Elective nodal RT Ipsilateral hilum No PFT limits No Yes Normal lung RT limits No Yes (V20 < 35%)
Timing of Thoracic Irradiation in LSCLC Thoracic radiation 40 Gy in 15fx Murray N et al, JCO 1993;11(2):336-44
Early Late 3 yr PFS 26% 19% P=0.036 Median survival 21.2 m 16 m P=0.008 Murray N et al, JCO 1993;11(2):336-44
Early vs Late Thoracic Radiation Sites of Failure No significant difference in thoracic recurrence: 50-60% recurrence at 2-3 yrs Significant difference in incidence of brain metastases Murray N et al, JCO 1993;11(2):336-44
Thoracic Radiation in LSCLC Meta-analysis 14% reduction in risk of death (p=.001) 5.4% (+/- 1.4%) absolute increase in 3 yr survival No significant difference if - Early or late thoracic radiation (< 60 days) - Sequential vs concurrent/alternating chemoradiation - Young (<55 yrs) vs old (>70 yrs) Pignon JP et al, NEJM 1992
Meta-Analysis of Timing of Chest Individual patient data RT in LSCLC Randomized trials (1969-2006) of chemort for LSCLC comparing early (before day 49) versus late RT short versus longer duration Primary endpoint was overall survival Secondary endpoints PFS, acute > gr 3 toxicities, chemotherapy compliance ( different if compliance between arms > 10%) De Ruysscher D et al, Abst M019.03, WCLC 2011
Meta-Analysis of Timing of Chest RT in LSCLC 9 trials with 2,304 patients Results OS HR early vs late = 1.00 (p=0.92) PFS HR early vs late = 0.93 (p=.14) Toxicity early > late (anemia, esophagus, cardiac) CT compliance: if similar early better than late De Ruysscher D et al, Abst M019.03, WCLC 2011
Meta-Analysis of Timing of Chest RT in LSCLC De Ruysscher D et al, Abst M019.03, WCLC 2011
Meta-Analysis of Timing of Chest RT in LSCLC Conclusions: Differences in CT compliance between arms mostly explains heterogeneity in outcome If CT compliance similar between the arms, then early RT associated with improved 5-yr survival De Ruysscher D et al, Abst M019.03, WCLC 2011
If you knew the correct dose and time What to treat?
Radiation fields prior to 2010 CALGB/RTOG Gross disease Ipsilateral hilum Precarinal Bilateral paratracheal Subcarinal Aortopulmonary + para-aoritic if L sided CONVERT Gross disease
Current Radiation Fields CALGB/RTOG Gross disease Ipsilateral hilum Precarinal Bilateral paratracheal Subcarinal Aortopulmonary + para-aoritic if L sided CONVERT Gross disease
Amin N et al. JTO 2011 (in press)
Chemotherapy often leads to GTV reduction and risk of RP Amin N et al. JTO 2011 (in press)
Pre-Chemo Post-Chemo V20 decreased from 71 to 36% NTCP decreased from 44 to 16% Green 45 Gy Red 49.5 Gy Brown 22.5 Gy Amin N et al. JTO 2011 (in press)
Small Cell Toxicity Pneumonitis/Pulmonary Study N % > Gr 3 Ettinger D et al, JCO 2005 RTOG 9609 45 Gy BID + CEP Turrissi A et al, NEJM 1999 Int 45 Gy BID vs. 45 Gy QD Hanna N et al, Lung Cancer 2002 45 Gy QD + VIP Schild SE et al, JCO 2007 60 Gy BID split Le Q et al, JCO 2009 61 Gy QD + CP + tirapazamine 55 9% 417 2% 53 9% 76 14.4% 68 2%
Correlation of normal lung RT and Radiation Pneumonitis > Gr 2 242 patients SCLC Sequential chemort 50 Gy standard fx 13% rate of symptomatic pneumonitis (needing drugs or hospitalization) Roeder F et al, Strahlenther Onkol 2010;186(3):149-56
Correlation of normal lung RT and RP > Gr 2 Nonsignificant factors V40 V10, 20, MLD V30 V20 V10 Age Gender Performance status Smoking history Tumor location FEV1 Roeder F et al, Strahlenther Onkol 2010;186(3):149-56
Prophylactic Cranial Irradiation (PCI) 5.4% Absolute improved survival at 3 yrs Auperin A et al, NEJM 1999;341:524-526
PCI 99-01 EORTC 22003-08004/RTOG 0212: Phase II/III study of PCI in LSCLC Stratify Age 1. <60 2. >60 Interval from Initial Tx 1. <90 2. 91-180 3. >180 Accrual goal 720 R A N D O M I Z E 2 1 1 Arm 1: 2.5 Gy qd x 10 fractions Total dose of 25 Gy Arm 2: 2.0 Gy qd x 18 Total dose 36 Gy Arm 3: 1.5 Gy bid x 24 Total dose 36 Gy Le Pechoux et al, Lancet 2009; 10:467-474
P=.05 25 Gy 36 Gy Le Pechoux et al, Lancet 2009; 10:467-474
RTOG 0212: Impact of PCI on Chronic Neurotoxicity 264 evaluable patients No difference in QOL between doses Neurocognitive decline by 12 months 62% 25 Gy arm 85-90% 36 Gy arms Higher toxicity if age > 60 yrs Standard of care for PCI for LSCLC: 25 Gy in 10 fractions Wolfson A et al, IJROBP 2011;81(1):77-84 Le Péchoux C et al. Ann Oncol 2011;22:1154-1163
Le Péchoux C et al. Ann Oncol 2011;22:1154-1163 The Author 2010. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: journals.permissions@oxfordjournals.org
Stereotactic Body Radiation Therapy (SBRT)
Stereotactic Body Radiation Therapy (SBRT) Breathing control is key Highly conformal Tight margins Pre-RT onboard imaging
Improved survival for surgery if N0 (SEER 1988-2002) Schreiber D, et al. Cancer 2010;116:1350-7
SBRT for Stage I Medically Inoperable SCLC 6 patients biopsy proven clinical T1N0M0 between 2004-2010 Plan was SBRT followed by platinum/etoposide followed by PCI SBRT dose varied (60 Gy/3 fx, 50 Gy/5 fx, 30 Gy in 1 fx) 100% local control, no regional node relapses Overall survival 63% at one year Disease free survival 75% at one year Videtic et al JTO 2011, 6(6): S1344
Role of Radiation Therapy in ESCLC RTOG 0937 4-6 cycles platin-based chemo Eligible ESCLC PS 0-2 No CNS mets 1-3 sites of mets CR or PR to chemo Stratify Response 1. CR 2. PR Number of Met Sites 1. 1 2. 2-3 Accrual Goal 154 R A N D O M I Z E Arm 1: PCI 2.5 Gy in 10 fx Arm 2: PCI 2.5 Gy 10 fx + Consolidative RT to Locoregional and Residual Metastatic Disease 45 Gy in 15 fx or 40 Gy in 10 fx
Extensive SCLC: Implications for Oligometastatic RT 115 ESCLC patients 2003-2010 90% had disease confined to 1-3 sites (30% brain metastases) Only 57 patients received > 2 cycles chemo 39 primarily chemo with RT for palliation (1 PCI) 18 chemo and consolidative chest RT (7 PCI) Chest RT associated with improved local control and survival (33% vs 21% at 1 yr, p=.0459) PCI associated with improved 1 yr brain mets rate (60% vs 13%, p=.0003) Devisetty et al JTO 2011, 6(6): S1343
Summary of Update - Limited RT Dose being studied RT Timing?benefit to early RT Volume controversial PCI Neurotoxicity quantified SBRT possible but rare - Extensive RT Oligometastatic being studied