six months for five years and then annually until year 10. The primary end-point is disease-free survival.
Randomised Double-blind Trial in Adjuvant Non-small-cell Lung Cancer with Tarceva Trial The RADIANT trial is a phase III clinical trial designed to evaluate the role of erlotinib in the adjuvant treatment of patients with resected stage IB–IIIA NSCLC (see Figure 5). The adjuvant trial is a double-blind, placebo-controlled study that randomised 945 patients to either two years of daily oral erlotinib therapy at 150mg/day or placebo. Only patients with EGFR-positive tumour tissue detected by either FISH or IHC were randomised. Before randomisation, patients were allowed to receive up to four cycles of platinum-based adjuvant chemotherapy. Correlates of the study include EGFR FISH and mutational status. RADIANT has completed accrual and we are awaiting results. Massachusetts General Hospital and the Dana Farber Cancer Institute are running a phase II non-randomised clinical trial evaluating erlotinib as an adjuvant therapy in patients with resected stage I–IIIA NSCLC with confirmed exon 19 deletion mutations or exon 21 L858R point mutations in the EGFR.
Tailored Post-surgical Therapy in Early-stage Non-small-cell Lung Cancer Trial
The TASTE trial is enrolling patients for a randomised phase II/III adjuvant trial, evaluating the feasibility of standard versus customised treatment in stage II or IIIA non-N2, non-squamous NSCLC (see Figure 6). Patients are randomised to receive either standard chemotherapy consisting of cisplatin plus pemetrexed for four cycles (Arm A) or a customised drug treatment in Arm B. In Arm B, patients harbouring EGFR mutations will be treated with erlotinib. If they have wild-type or an undetermined EGFR status, patients will be tested for their levels of ERCC1. Those that have high ERCC1 levels will receive no treatment and be observed and those that have low ERCC1 levels will receive cisplatin plus pemetrexed for four cycles. The hypothesis is that patients receiving tailored adjuvant therapy will have better disease-free survival rates than patients in the control arm receiving standard chemotherapy therapy.
Spanish Customised Adjuvant Trial
The Spanish customised adjuvant (SCAT) trial uses the BRCA1 mRNA levels to customise therapy in patients with completely resected stage I–IIIA NSCLC (see Figure 7). The rationale for the trial is that patients with low BRCA1 mRNA levels have longer survival when
1. Mountain CF, Revisions in the International System for Staging Lung Cancer, Chest, 1997;111:1710–7.
2. Arriagada R, Bergman B, Dunant A, et al., Cisplatin-based adjuvant chemotherapy in patients with completely resected non-small-cell lung cancer, N Engl J Med, 2004;350:351–60.
3. Douillard JY, Rosell R, De Lena M, et al., Adjuvant vinorelbine plus cisplatin versus observation in patients with completely resected stage IB–IIIA non-small-cell lung cancer (Adjuvant Navelbine International Trialist Association [ANITA]): a randomised controlled trial, Lancet Oncol, 2006;7:719–27.
4. Winton T, Livingston R, Johnson D, et al., Vinorelbine plus cisplatin vs. observation in resected non-small-cell lung cancer, N Engl J Med, 2005;352:2589–97.
5. Pignon JP, Tribodet H, Scagliotti GV, et al., Lung adjuvant cisplatin evaluation: a pooled analysis by the LACE Collaborative Group, J Clin Oncol, 2008;26:3552–9.
6. Burdett S, Stewart LA, Rydzewska L, A systematic review and meta-analysis of the literature: chemotherapy and surgery versus surgery alone in non-small cell lung cancer, J Thorac Oncol, 2006;1:611–21.
7. Burdett SS, Stewart LA, Rydzewska L, Chemotherapy and surgery versus surgery alone in non-small cell lung cancer, Cochrane Database Syst Rev, 2007:CD006157.
treated with cisplatin-based chemotherapy,49 whereas patients
with high BRCA1 levels have longer survival when treated with taxane-based therapy.50
levels had significantly worse survival.33
Early-stage NSCLC patients with high BRCA1 The trial was designed to give
patients with high BRCA1 levels docetaxel, patients with intermediate BRCA1 levels docetaxel/cisplatin, and patients with low BRCA1 levels cisplatin/gemcitabine. An interim analysis presented at the American Society of Clinical Oncology in 2008 showed that single-agent docetaxel had no detrimental effect on survival compared with docetaxel/cisplatin.
International Tailored Chemotherapy Adjuvant Trial The International tailored chemotherapy adjuvant (ITACA) trial is a pharmacogenetic-driven phase III study based on both ERCC1 and TS testing (see Figure 8). The study selects adjuvant therapy for patients with resected stage II and IIIA NSCLC based on RT-PCR expression of ERCC1 and TS. ERCC1 and TS are scored as either high or low and the four possible combinations of expression levels are treated with different chemotherapy. The four chemotherapy possibilities are taxane (ERCC1 high and TS high), pemetrexed (ERCC high and TS low), cisplatin/gemcitabine (ERCC1 low and TS high) and cisplatin/pemetrexed (ERCC1 low and TS low). Each of the four customised chemotherapy regimens is being tested against a control arm consisting of a cisplatin-doublet of the investigator’s choice.
The use of chemotherapy for the treatment of patients with resected NSCLC became the standard of care less than a decade ago; however, we appear to have reached a plateau in efficacy. The benefits of empiric treatment were modest with a 5–10% improvement in overall survival at five years. Increased interest in identifying biomarkers has led to retrospective analysis of biomarkers from completed trials. Close analysis of the adjuvant chemotherapy trials revealed that subgroups of patients carrying differential expression or mutation of a particular gene resulted in different outcomes. Those biomarkers are now being used in prospective randomised controlled clinical trials to determine if they have utility as predictive biomarkers. In addition, combinations of genes are being explored as a genetic profile for individualising therapy. With improved understanding of the basic biology behind NSCLC and more drugs targeting pathways actively contributing to tumour growth, we are beginning to enter the era of personalised adjuvant therapy. The results of these ongoing trials will hopefully lead to improved care for our patients in the near future. n
8. Holmes EC, Preoperative neoadjuvant therapy in non-small- cell lung cancer: open season? J Natl Cancer Inst, 1991;83: 228–9.
9. Chemotherapy in non-small cell lung cancer: a meta-analysis using updated data on individual patients from 52 randomised clinical trials. Non-small Cell Lung Cancer Collaborative Group, BMJ, 1995;311:899–909.
10. Chhatwani L, Cabebe E, Wakelee HA, Adjuvant treatment of resected lung cancer, Proc Am Thorac Soc, 2009;6:194–200.
11. Scagliotti GV, Fossati R, Torri V, et al., Randomized study of adjuvant chemotherapy for completely resected stage I, II, or IIIA non-small-cell lung cancer, J Natl Cancer Inst, 2003;95:1453–61.
12. Waller D, Peake MD, Stephens RJ, et al., Chemotherapy for patients with non-small cell lung cancer: the surgical setting of the Big Lung Trial, Eur J Cardiothorac Surg, 2004;26:173–82.
13. Gandara DR, Lara PN Jr, Mack P, et al., Individualizing therapy for non-small-cell lung cancer: a paradigm shift from empiric to integrated decision-making, Clin Lung Cancer, 2009;10:148–50.
14. Custodio AB, Gonzalez-Larriba JL, Bobokova J, et al., Prognostic and predictive markers of benefit from adjuvant chemotherapy in early-stage non-small cell lung cancer, J Thorac Oncol, 2009;4:891–910.
15. Ikeda N, Nagase S, Ohira T, Individualized adjuvant chemotherapy for surgically resected lung cancer and the roles of biomarkers, Ann Thorac Cardiovasc Surg, 2009;15:144–9.
16. Simon GR, Individualizing chemotherapy for non-small cell lung cancer (NSCLC) in the adjuvant and advanced setting: current status and future directions, Curr Treat Options Oncol, 2008;9:300–12.
17. Simon G, Sharma A, Li X, et al., Feasibility and efficacy of molecular analysis-directed individualized therapy in advanced non-small-cell lung cancer, J Clin Oncol, 2007;25:2741–6.
18. Olaussen KA, Dunant A, Fouret P, et al., DNA repair by ERCC1 in non-small-cell lung cancer and cisplatin-based adjuvant chemotherapy, N Engl J Med, 2006;355:983–91.
19. Simon GR, Sharma S, Cantor A, et al., ERCC1 expression is a predictor of survival in resected patients with non-small cell lung cancer, Chest, 2005;127:978–83.
20. Zheng Z, Chen T, Li X, et al., DNA synthesis and repair genes RRM1 and ERCC1 in lung cancer, N Engl J Med, 2007;356:800–8.
21. Bepler G, Kusmartseva I, Sharma S, et al., RRM1 modulated in vitro and in vivo efficacy of gemcitabine and platinum in non- small-cell lung cancer, J Clin Oncol, 2006;24:4731–7.
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