NSCLC: Staging & Prognosis. Neoadjuvant chemotherapy. Controversies in the management of early NSCLC: neoadjuvant vs adjuvant chemotherapy

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1 Controversies in the management of early NSCLC: neoadjuvant vs adjuvant Sarita Dubey sst Professor, Medical ncology, UCSF NSCLC: Staging & Prognosis Pathologic Survival elapse (%) Stage 5 yr (%) Local Distant I T1M IB T2M II T1N1M IIB T2N1M T3M 38 III T3N1M T1-3N2M 23 Mountain CF. Chest.1997;111: ; Feld, et al. J Clin ncol. 1984;2: ; Pairolero PC, et al. nn Thorac Surg. 1984;38: ; Martini N, Melamed M. J Thorac Cardiovasc Surg. 198;3: ; Thomas P, ubinstein L. nn Thorac Surg. 199;49: ; Goldstraw P, et al. J Thorac ncol. 27;2: Improving survival rates with Systemic therapy in a local disease Neoadjuvant NEDJUVNT CHEMTHEPY DJUVNT CHEMTHEPY S 99 MC LU22 / NVLT / ETC 812 IB-III N D M I Z E PCLITXEL CBPLTIN (PCb) x 3 cycles SUGEY Mediastinoscopy if LN > 1 cm on CT Pisters K, et al. J Clin ncol. 27;25(18S). bstract 752. SUGEY Closed 24 because of adjuvant data Final accrual 354/6 18 ineligible Induction N =258 IB - III : /vinorelbine 45% /gemcitabine 25% Carboplatin/docetaxel 12% Gilligan D, et al. Lancet. 27;369: N=261 76% received all 3 cycles of 4% C 45% P Closed early 1

2 for Early Stages Trial (Ch.E.S.T.) Stratification IB/II vs. IIB/III (T3N1 excluding superior sulcus) Mediastinoscopy for MLN >1cm N D M IZ TI N rm 1: rm 2: 75 mg/m2, d.1 Gemcitabine 125 mg/m2 d.1&8, Q 3wks x 3 cycles 1 objective : 3-PFS / Gemcitabine CLSED ELY ccrual 27 / 7 Scagliotti, SC 28,# 759 F LL WŪ P Induction phase III trials Trial Stage n S99 LU-22 Ch.E.S.T. IB-II 354 Carbo/paclitaxel I-III 519 Platinum-doublet IB-III 27 Cis/gemcitabine Surg 42% 45% IB/II 7 IIB/III 47% 5yr S surg 48% H.83( 95% CI ) P=.24 44% H1. (95% CI ) 65% 7 p=.1 CLSED ELY NEGTIVE ESULTS No significant increase in postop morbidity with induction MC LU22 / NVLT / ETC 812 (n = 261) + (n = 258) % Men / Squamous 72% / 48% 72% / 51% I/IB 15% / 44% 19% / 45% resection Pneumonectomy Lobectomy 79% 28% 5 81% 23% 56% Surgical Morbidity 43% 38% 2-yr PFS 52% 53% (H =.96) LU22 SWG 5-yr S 45% 44% (H = 1.2) ChEST Gilligan D, et al. Lancet. 27;369: Meta-analyses on neoadjuvant therapy Conclusions Berghmans Lung Ca 25, 49,13-23 Huang PSC 25; 23 bstr # 7265 Burdett JT 26, 1: CT s N = 8 CT s N= CT s N=988 verall survival H.66 (CI ) in favor of neoadjuvant chemo H.68 (CI ) Higher quality trials H.8 (CI ) 5yr S 6% H.82 (CI ) P=.2 Neoadjuvant is a promising modality to improve outcomes in early lung cancer esults are blunted by early closure of clinical trials Better tolerability of preoperatively Induction does not increase surgical morbidity 2

3 djuvant Platinum-Based CTs djuvant Study Stage N LPI I-III 129 Cis / Mito / Vindesine BLT I-III 488* Cis regimen (1 of 4) CLGB I-III IB * Cis/ Vincaor Etoposide JB.1 IB-II 482 Cis / NIT I-III 84 Cis / Carbo / Paclitaxel esult Negative Negative Pos Neg *Failed to complete goal enrollment. Proportion Surviving NIT: + (CV) Median (mo) P value H (95% CI) BS CV ( ) bs.25 CV verall survival improvement at 5 years (8.6%) maintained at 7 years (8.4%) Months Douillard JY, et al. Lancet ncol. 26:7; N = 84 Proportion Surviving 1 JB.1: + djuvant Vin / Cis Median survival 2 Vin / Cis 94 months vs observation 73 months (H =.69; 95% CI ; P =.4) N = 482 Winton T, et al. N Engl J Med. 25;352: JB.1: Exploratory nalysis of Disease-Specific Survival by ge 65 years, n = 327 > 65 years, n = 155 Despite a statistically significantly lower dose intensity (by ~), the older group experienced a similar benefit as the younger Pepe C, et al. J Clin ncol. 27;25: ELIGIBLE: esected Stage I-III No prior chemo No T N D M I Z E Primary endpoint = overall survival rriagada, et al. N Engl J Med. 24;35: No adjuvant with one of the following: vindesine vinorelbine vinblastine etoposide 3

4 1 - verall Survival H=.86 [ ] p<.3 fter longer follow up : 7.5 yrs 5yrS 44.5% S+C S Control rriagada, NEJM 35:351, 24 1 verall survival control deaths deaths before 5 years - 56 deaths after 5 years : 578 deaths deaths before 5 years - 83 deaths after 5 years H:.91 ( , p.1) years Le Chevalier T, J Clin ncol. 28(May 2 suppl). bstract Distant metastases rate control: 378 events p=.2 : 338 events years Second malignancies 1 Non-lung cancer mortality Control control: 57 events p=.54 : 5 events years Cumulative Incidence(%) H: 1.34 p= >8 4

5 Comparison with other CT trials Comparison with other CT trials NIT VP16 57% Med age 61 Stage III PT 3 27% Pneumo nectomy 34% 37% 5yrS 4.5% 8.6% 7yrS H (>5yr) % NIT VP16 57% Med age 61 Stage III PT 3 27% Pneumo nectomy 34% 37% 5yrS 4.1% 8.6% 7yrS H (>5yr) % JB-1 24% 15% N JB-1 24% 15% N Lung djuvant Evaluation (LCE) Meta-analysis of adjuvant cisplatin trials performed since 1995 BLT, LPI,, JB.1, NIT Pooled individual patient data 4584 resected patients, 5 randomized trials 7% Stage I 3 Stage IB 36% Stage II 27% Stage III Pignon JP, et al. J Clin ncol. 28;26: LCE: verall Survival No Deaths Hazard atio Trial / No Entered ( / Control) H (95% [95% CI] CI) LPI 569 / [.81;1.12] NIT 458 / [.68;.98] BLT 186 / [.71;1.27] 98 / [.8;1.4] JB1 197 / [.54;.94] Total 239 / better Control better effect Pignon JP, et al. J Clin ncol. 28;26: P =.5.89 [.82;.96] (.82;.96] LCE nalysis by Stage Category No. Deaths / No. Entered Hazard atio ( / Control) H [95% CI] Stage I 14 / [.96;2.9] Stage IB 515 / [.78;1.1] Stage II 893 / [.73;.95] Stage III 878 / [.73;.95] better Control better djuvant chemo has greatest benefit for stage II and III and may be detrimental for stage I Pignon JP, et al. J Clin ncol. 28;26: Test for trend: P =.51 Probability CLGB 9633: Carboplatin+Paclitaxel in Stage IB MS P value H (9 CI) 95 months.1.8 (.6-1.7) 78 months Survival Time () Strauss GM, et al. J Clin ncol. 26;24(18S). bstract 77. 5