NSCLC, non-small-cell lung cancer. Historically, when oncologists find something is effective for patients with advanced disease, it is then moved up earlier in the treatment paradigm. The median 1-year and 2-year survival has been affected tremendously for patients with advanced NSCLC during the past 20 or 30 years with chemotherapy. Since chemotherapy can affect patients with big, bulky metastatic disease, the question is whether chemotherapy affects patients with micrometastatic disease.
CI, confidence interval; Cis, cisplatin; HR, hazard ratio; NSCLC, non-small-cell lung cancer; obs, observation; OS, overall survival ; Vin, vinorelbine. The JBR.10 also recently updated its survival results and found that the survival benefit with adjuvant chemotherapy did persist. The median overall survival on the chemotherapy arm was 7.8 years whereas it was 6.0 years on the observation arm, with a hazard ratio of 0.8 and a P value of .04. They did find a higher incidence of disease-related deaths on the observation arm and they did not, unlike the IALT study, find a higher incidence in nondisease-related deaths between the 2 arms.
BALKAN MCO 2011 - T. Cufer - Adjuvant/neo adjuvant systemic therapy in NSCLC
Adjuvant / Neo-adjuvant Systemic Therapy of NSCLC Tanja Cufer, MD, PhD University Clinic Golnik Medical Faculty Ljubljana, Slovenia ESO Masterclass, Dubrovnik 2011
Does Chemo Work for Stage IV NSCLC? Yr Median Survival, Mos 1-Yr Survival, % 2-Yr Survival, % 1980s 4-6 10 -- 2000 8 30-35 10-15 2005 (adeno, no brain mets) 12 50 20
What After Radical Loco-regional Therapy in Operable NSCLC ?
Meta-Analysis on the Role of Chemotherapy in NSCLC Absolute benefit with cisplatin containing regimens Non-Small Cell Lung Cancer Collaborative Group. BMJ. 1995;311:899 . S ± CT S + RT ± CT 2 years 3% 2% 5 years 5% 2%
Lung Adjuvant Cisplatin Evaluation (LACE): a Pooled Analysis of 5 Randomized Trials Pignon JP, et al. J Clin Oncol, 2008;26:3552. Absolute benefit of 5.4% at 5 years Absolute benefit of 5.8% at 5 years
LACE: Other Factors <ul><li>Effect of chemotherapy on overall and disease-free survival did not vary according to age, gender, performance status, histology, type of surgery, planned radiotherapy, planned total dose of cisplatin </li></ul>
Collaborative Group Meta-Analys e s <ul><li>Surgery + CT vs surgery alone </li></ul><ul><li>1995 </li></ul><ul><ul><li>14 trials available (8 trials cisplatin based) </li></ul></ul><ul><ul><li>4357 patients </li></ul></ul><ul><li>20 10 </li></ul><ul><ul><li>3 4 trials available </li></ul></ul><ul><ul><li>8 4 47 patients </li></ul></ul>NSCLC Meta-analysis Collaborative Group, Lancet 2010; 375: 1267
Overall Survival (S +/- Ct) Patients at Risk Surg alone Surg+chemo 4068 3585 3043 2539 2034 1548 779 358 103 4079 3607 3074 2584 2137 1665 835 389 108 % Survival 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 Survival Time, years 0 1 2 3 4 5 6 7 8 HR: 0.87 (0.81-0.93), P <.0000001 Absolute benefit at 5 years 4%, from 60% to 64% Surg alone Surg + chemo
Survival by Stage Exploratory analysis STAGE I 717/2659 881/2694 II 311/652 353/654 IIIA 428/710 398/652 IIIB / IV 21/39 25/50 [no. events/no. entered ] Surg+chemo Surg alone Hazard Ratio (Fixed) Analysis prespecified in protocol When 89 IIIb/IV patients removed, trend p=0.178 Trend P = .05 Trend P = .208 STAGE IA 185/1028 228/982 IB 450/1308 519/1353 IIA 59/136 62/119 IIB 290/573 337/613 IIIA 239/394 218/341 IIIB / IV 15/28 23/40 Surg+chemo Better Surg alone Better 0 1 2 0.5 1.5
Overall Survival (S + Rt +/- Ct) Patients at risk CT 1315 711 385 203 84 Control 1345 660 376 202 85 % Survival Survival Time, years HR = 0.89 (95%CI: 0.81-0.97), P = .009 0.0 0.2 0.4 0.6 0.8 1.0 0 2 4 6 8 CT Control Absolute benefit at 5 yrs 4% , from 29% to 33%
2010 Meta-analysis: Other Factors <ul><li>Effect of chemotherapy did not vary according to age, gender, histology, performance status or stage </li></ul><ul><li>Addition of adjuvant chemotherapy improves survival irrespective of whether Cht is adjuvant to surgery alone or to surgery plus radiotherapy </li></ul>
R Chemotherapy Control Thoracic Radiotherapy 60 Gy (optional, predefined according to N stage) Stratified by center, stage and type of surgery Long-Term Results of the International Lung Cancer Trial Evaluating Adjuvant Cisplatin-Based Chemotherapy in Resected NSCLC IALT Trial Design
Overall Survival 935 775 619 520 447 372 282 208 125 932 780 650 550 487 399 300 208 133 0% 20% 40% 60% 80% 100% 0 1 2 3 4 5 6 7 8 years Chemotherapy: 578 deaths - 495 deaths before 5 years - 83 deaths after 5 years Control 590 deaths - 534 deaths before 5 years - 56 deaths after 5 years HR = 0.91 [0.81-1.02] P = .10 Le Chevalier T, et al. J Clin Oncol . 2008;26(May 20 Suppl): Abstract 7507.
IALT: Causes of Mortality Arrigada et al, et al. J Clin Oncol . 2010;28
JBR.10 Design R Platinum / vinorelbin Control No Thoracic Radiotherapy RESECTED NSCLC Stratified by center, stage and type of surgery Butts CA, et al. J Clin Oncol . 2010, vol 28 Long-Term Results of the JBR.10 Trial Evaluating Adjuvant Chemotherapy with Cisplatin / Vinorelbin
JBR.10: Updated OS and Survival by Stage and T Size <ul><li>Long-term (> 9 years median follow-up) OS superior with chemotherapy vs observation </li></ul><ul><li>Median OS: 7.8 years vs 6 years with chemotherapy vs observation, respectively </li></ul><ul><ul><li>HR: 0.78 (95% CI: 0.61-0.99; P = .04) </li></ul></ul><ul><li>Benefit persists > 12 yrs </li></ul><ul><ul><li>May be limited to stage II and bulky (≥ 4 cm) stage IB NSCLC </li></ul></ul>Vincent MD, et al. ASCO 2009. Abstract 7501. <ul><li>Significantly higher cumulative incidence of disease-related deaths with obs vs chemo ( P = .027) but nondisease-related death rates similar between arms ( P = .660 ) </li></ul>Disease Stage Median OS, Yrs Vin/Cis Obs P Value Stage II 6.8 3.6 .01 Stage IB 9.8 11.0 .87 <ul><li>T < 4 cm </li></ul>7.6 11.2 .07 <ul><li>T ≥ 4 cm </li></ul>NR 9.8 .13
J BR.10: Causes of Mortality Butts CA, et al. J Clin Oncol . 2010, vol 28
Meta-analysis of Neoadjuvant Chemotherapy in Resectable NSCLC Crino et al, Ann Oncol 2010; 21:103 Twelve per cent relative survival benefit with the addition of neoadjuvant chemotherapy (1507 patients; HR = 0.88; P = 0.07), equivalent to an absolute improvement in survival of 5% at 5 years.
Stage IIIA Disease <ul><li>Accounts for approx. 30% of patients </li></ul><ul><li>Wide range of pathological conditions: from resectable tumors with occult nodal involvement to bulky multistational nodal disease </li></ul><ul><li>The wide range of treatment possibilities: </li></ul><ul><li>From curative treatment to best supportive care </li></ul><ul><li>From single modality to trimodalities </li></ul><ul><li>Require a multidisciplinary approach in most cases </li></ul>
III (pN2) Disease Is Heterogeneous <ul><li>N2(1) : Incidental nodal metastases found on final pathologic examination of the resection specimen </li></ul><ul><li>N2(2) : Nodal metastases recognized only intraoperatively </li></ul><ul><li>N2(3) : Nodal metastases, single or multistation, recognized on prethoractomy staging (potentially resectable) </li></ul><ul><li>N2(4) : Bulky or fixed multistation disease </li></ul>One Proposed Subset Classification Robinson LA, et al. Chest . 2003;123(1Suppl):202S-220S.
Randomized Trials on “Adding Surgery to Induction Therapy” in Functionally Operable Stage IIIA No statistical difference in survival 1. Albain KS, et al. J Clin Oncol. 2005;23(16S): Abstract 7014. 2. van Meerbeeck JP, et al. J Natl Cancer Inst. 2007;99 (6):442-450. 3. Improved local control with surgery, and improved survival in patients opted for lobectomy ! Trial Treatment Patients Median Survival, Months 5-Yr Survival % Intergroup 1 R+C S C R+C C 202 194 23.6 22.2 27.2 20.3 EORTC 2 C Resp R S 165 167 17.5 16.4 14 15.7
J BR.19 Trial : Adjuvant Gefitinib vs. Placebo <ul><li>No significant difference in DFS and OS </li></ul><ul><li>Shortages: </li></ul><ul><ul><li>Unselected population of NSCLC </li></ul></ul><ul><ul><li>Median duration of gefitinib therapy: 4 months </li></ul></ul>Goss et al, ASCO 2010, Abst. 7005
ERCC1 negative Adjusted HR = 0.65, 95%CI [0.50-0.86], P = .002 Effect of Adjuvant Chemotherapy According to ERCC1 Status , IALT Bio ERCC1 positive Adjusted HR = 1.14, 95%CI [0.84-1.55], P = .40 Olaussen K, et al. N Engl J Med. 2006;355(10):983-991 .
Ongoing Clinical Trials <ul><li>ECOG: Cht +/- bevacizumab </li></ul><ul><li>RADIANT: KT +/- erlotinib </li></ul><ul><li>TASTE: Cht vs erlotinib by ERCC1, EGFRmu </li></ul><ul><li>ITACA: Cht by ERCC1, TS </li></ul><ul><li>SWOG: Cht yes/no by ERCC1, RMM1 </li></ul><ul><li>ECOG: Cht yes/no by gene signature </li></ul><ul><li>MAGE-A3: Cht yes/no +/- vaccine </li></ul><ul><li>NCT0125 : Carbo/pem vs Carbo/vinorelbin </li></ul>
Conclusions <ul><li>Adjuvant cisplatin-based chemotherapy represents the standard of care for stage II and III NSCLC. </li></ul><ul><li>Its role in stage I B disease is not yet clear, there are data (JBR.10, 2010 Meta-analysis) suggesting that it might be effective in larger tumors (≥ 4 cm) </li></ul><ul><li>The benefit observed in individual trials and in meta-analyses suggests the use of 4 cycles of modern platinum-based doublets in absence of comorbidities </li></ul><ul><li>Long-term effects of chemotherapy should be analyzed in all randomized trials </li></ul><ul><li>Further progress is foreseen by tailoring adjuvant systemic therapy according to biomarkers and by introducing new targeted agents </li></ul>