The standard of care with regard to adjuvant chemotherapy of lung cancer has changed remarkably over the past 3 years. Until the initial report of the International Adjuvant Lung Trial in 2003, there was no real evidence from any individual randomized clinical trial (RCT) that adjuvant chemotherapy improves survival in resectable non-small-cell lung cancer. However, five RCTs that have now been reported indicate that adjuvant chemotherapy is effective, at least in certain subgroups of resectable patients. Moreover, numerous meta-analyses have also reported a positive effect from adjuvant treatment. Nonetheless, because of methodologic issues and conflicting results, the question of who should be treated and what constitutes optimal adjuvant therapy remains controversial. This article reviews the recent randomized trials that have contributed to a change in the state of the art, as well as some of the methodologic problems that may have confounded their proper interpretation. It also considers newer approaches to adjuvant therapy, with a particular focus on strategies that incorporate our growing knowledge of molecular medicine and predictive factors to the field of adjuvant chemotherapy of lung cancer.
Following the results of the last generation of randomized trials, adjuvant chemotherapy is now a standard treatment in non-small-cell lung cancer (NSCLC), confirming the findings of the individual patient data meta-analysis published in 1995. It took more than 25 years to demonstrate the effect of chemotherapy in this setting, long after similar demonstrations in colon and breast cancer. Thus, the question is no longer "should adjuvant chemotherapy be given in resected NSCLC?" but rather, "how long will the medical community need to standardize, optimize, and individualize this approach?" The current debate concerns which patients benefit from this treatment and which drugs should be used.
The available high-quality evidence comes first from trials of cisplatin-based chemotherapy for 3 months, which were evaluated mostly in Western countries in stage IB, II, and IIIA NSCLC,[2-8] and second, from trials of oral uracil/tegafur (UFT) for at least 1 year, performed in Japan on a population including 96% patients with stage I disease and more than 80% with adenocarcinoma.
The Lung Adjuvant Cisplatin Evaluation (LACE) study is a pooled analysis of the individual data of the five largest trials on adjuvant cisplatin-based chemotherapy,[2-6] which aimed to identify trials or patient characteristics linked to chemotherapy effects. Based on its results, the effect of cisplatin-based chemotherapy in stage II and IIIA NSCLC is clearly shown. The number of patients treated with stage IA disease was too small to draw any conclusions. The effect of chemotherapy in the subgroup with stage IB was not significant, which argues against an effect. Nevertheless, the test of interaction between stage IB, II, and III is not significant (although powerful) in a population of more than 4,500 patientsa strong argument in favor of an effect in stage IB disease.
Of note, the updated results of the Cancer and Leukemia Group B (CALGB) trial 9633 are fully compatible with stage IB findings in the LACE study, as the confidence intervals of the corresponding hazard ratios of death largely overlap. To evaluate treatment effect in subgroups of patients, the recommended method is to compare results between the different subgroups using an interaction test and not to perform an analysis in each subgroup.[10,11] The limitation of the test of interaction is its lack of power, but this is not an issue in a large population such as in LACE. Since P values are more dependent on the size of subgroups or trials, overemphasis on P value should be avoided, and estimates of treatment effect with confidence intervals (indicating precision) should be reported.
The question about chemotherapy effect in early-stage NSCLC is similar to the ongoing debate in the setting of stage II colon cancer. Inclusion of stage IB patients in trials by those not convinced of an effect in this group as well as the search for prognostic factors of high risk of recurrence in this population will help to clarify this issue. The updated results of the NSCLC meta-analysis (NSCLC-MA) in approximately 10,000 patients and more than 30 trials should settle this issue when they become available in 2007.[1,14]
Concerning the choice of cisplatin-based chemotherapy, the LACE results did not favor a triplet with mitomycin; the doublet vinorelbine/cisplatin offered more promising results. But we should be careful in interpreting the comparison of the results between cisplatin/vinca alkaloid/etoposide and cisplatin/vinorelbine doublets. The population included in the different trials may be different. The different doses of cisplatin may also explain the difference in results between the doublets. Can we extrapolate the results of third-generation chemotherapy in metastatic disease to the adjuvant setting? Our opinion is that new trials are needed to demonstrate any benefit of these drugs, including gemcitabine (Gemzar), docetaxel (Taxotere), and pemetrexed (Alimta).
Role of UFT
The individual patient data meta-analysis on UFT included 2,003 patients, but its power is limited, as only 477 deaths occurred. A treatment effect has been demonstrated for the drug in both stage IA and IB NSCLC, and the absence of difference in the treatment effect between adenocarcinoma and squamous cell carcinoma needs to be confirmed. UFT is not available in Europe and the United States for adjuvant treatment. It would be important to confirm the benefit of UFT in the adjuvant setting in non-Japanese populations before it is introduced in adjuvant regimens elsewhere. Randomized trials in squamous cell carcinoma would also be helpful.
One other important step in establishing drug usefulness is to demonstrate that the drug has efficacy in large populations and not only in highly selected trial populations. Based on the Hamada et al study, we can consider UFT effective in stage I adenocarcinoma. The NSCLC-MA update will confirm whether cisplatin-based chemotherapy is effective in this setting. We consider the individual patient data meta-analysis to offer the best available evidence, as it allows data-checking, updates based on follow-up, standardized reanalysis of trials, and detailed exploration of the factors associated with treatment effectin particular, subgroup analyses.[16,17] For instance, it will allow the use the same definition of stage in all trials and report all the results presented with their 95% confidence intervals. Moreover, observational cohorts and information on the types of adjuvant chemotherapy regimens used in the community are warranted to elucidate the practical prescription of chemotherapy in daily practice.
Further issues in the adjuvant treatment of NSCLC include: How can we improve the efficacy of drug regimens? What is the best schedule and duration of adjuvant chemotherapy? What is the place of neoadjuvant chemotherapy? What is the place of adjuvant radiotherapy? How do we adapt treatment to the likely different diseases included under the umbrella of NSCLC (stage subgroup, different histology, different molecular classification, etc)? How do we speed up the process of adjuvant treatment evaluation? What are the long-term consequences of adjuvant chemotherapy? How do we manage the challenge of lung cancer epidemics in developing countries?
Future trials may include new drugs (gemcitabine, pemetrexed, taxanes) and molecularly targeted agents, for example, as maintenance after adjuvant chemotherapy or combined with chemotherapy, particularly if these agents demonstrate activity in NSCLC. The use of orally administered drugs such as anti-epidermal growth factor receptor (EGFR) therapy (erlotinib [Tarceva], gefitinib [Iressa]) or antiangiogenic therapy (eg, vascular endothelial growth factor-specific antibody bevacizumab [Avastin]) could be promising in the adjuvant setting. Table 1 gives examples of ongoing adjuvant trials. Studies of molecular target such as epidermal growth factor protein expression, amplification, and mutation must be integrated in such trials. In recent studies among patients with NSCLC who receive erlotinib or gefitinib, the presence of an EGFR mutation, EGFR amplification, or EGFR expression could predict responsiveness to the drug.[18,19]
Compared to adjuvant chemotherapy trials, the number of patients included in neoadjuvant trials has been limitedaround 2,000 vs 10,000 patients. The results of several large neoadjuvant trials are awaited and will probably confirm the meta-analysis. The comparison of adjuvant and neoadjuvant chemotherapy, as in the NATCH trial, or the addition of neoadjuvant chemotherapy to adjuvant chemotherapy will be the next areas of investigation.
Concerning postoperative radiotherapy, recent nonrandomized studies demonstrate a beneficial effect of such treatment in N2 disease. A European trial called Lung-ART comparing conformational radiotherapy to no irradiation in N2 disease will be launched very soon.
Adjuvant chemotherapy improves survival of patients with stage IB, II, and III NSCLC, but the benefit is probably not equal for all patients. Molecular characteristics of the cancer affect sensitivity to chemotherapy and are prognostic of the disease course. We can likely expect that different forms of NSCLC, with different prognostic features, biologic basis, and chemo-sensitivity, will be identified in the near future. This may result in different treatments, targeted or not, having greater effects. If our knowledge of disease biology allows us to design trials of a very efficient drug in a well-defined population, then smaller patient populations will be sufficient to demonstrate such effects.
However, only large trials will allow us to demonstrate that a targeted drug is useful only in patients with the target present. For instance, the Canadian BR.21 trial, a good-size trial for patients with advanced disease, failed to demonstrate that erlotinib has a better effect on survival in patients with advanced disease expressing EGFR, possibly because of insufficient power. There is also the risk of missing an interesting effect in patients whose disease does not express the markers.
We are still far from tailoring treatment to each patient. Rigorous methods are needed to demonstrate a predictive value of gene-expressing profiling, and the first results in breast cancer have led to large confirmatory trials such as TAILOR and MINDACT. Demonstration that tumor markers have predictive value in terms of treatment effects requires large trials and intergroup collaborations to validate them. For instance, the International Adjuvant Lung Trial (IALT) Bio-Program , which uses immunohistochemistry to determine various biologic markers, attempts to identify the best candidates for adjuvant chemotherapy and plans to validate its results in other trials.
Based on the previous experience of finding that adjuvant long-term treatment with an alkylating agent and radiotherapy has a deleterious effect in patients with NSCLC, the study of chemotherapy effects after 5 years is needed.
The lung cancer epidemic is slowing down in the Western world, and most patients with lung cancer live in countries that cannot afford the high cost of the new generation of treatment. This should be kept in mind when looking for the next treatment for lung cancer.
We have reached a new era of adjuvant therapy in NSCLC. The results of recent trials and meta-analyses have changed the treatment of patients with early-stage NSCLC, and adjuvant chemotherapy is the new standard of treatment for patients. But since the observed benefit is still small, more resources should be devoted to research in this setting, as it represents a major worldwide health problem. A reinforced international collaboration will allow research to be sped up by defining priorities and performing large studies with short delays. In the future, third-generation drugs and molecular-targeted therapies may also be part of the protocols for perioperative therapy in patients with early-stage NSCLC.
Jean-Pierre Pignon, MD, PHD
Christophe Massard, MD, MSC
Pierre Fabre Oncology paid Dr. Pignon's travel expenses for the 2006 annual ASCO meeting.
1. Non-Small Cell Lung Cancer Collaborative Group: Chemotherapy in non-small cell lung cancer: A meta-analysis using updated data on individual patients from 52 randomized clinical trials. BMJ 311:899-911, 1995.
2. Scagliotti G, 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 95:1453-1461, 2003.
3. International Adjuvant Lung Cancer Trial Collaborative Group: Cisplatin-based adjuvant chemotherapy in patients with completely resected non-small cell lung cancer. N Engl J Med 350:351-360, 2004.
4. Waller D, Peake RJ, 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 26:173-182, 2004.
5. Winton T, Livingston R, Johnson D, et al: Vinorelbine plus cisplatin vs observation in resected non-small-cell lung cancer. N Engl J Med 352:2589-2597, 2005.
6. Douillard J-Y, 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 randomized controlled trial. Lancet Oncology 7:719-727, 2006.
7. Strauss GM, Herndon JE, Maddaus MA, et al: Adjuvant chemotherapy in stage IB non-small cell lung cancer (NSCLC): Update of Cancer and Leukemia Group B (CALGB) protocol 9633 (abstract 7007). J Clin Oncol 24(18S):365s, 2006.
8. Pignon J, Tribodet H, Scagliotti J, et al: Lung Adjuvant Cisplatin Evaluation (LACE): A pooled analysis of five randomized clinical trials including 4,584 patients (abstract 7008). J Clin Oncol 24(18S):366s, 2006.
9. Hamada C, Tanaka F, Ohta M, et al: Meta-analysis of postoperative adjuvant chemotherapy with tegafur-uracil in non-small-cell lung cancer. J Clin Oncol 23:4999-5006, 2005.
10. Rothwell PM: Treating individuals 2. Subgroup analysis in randomised controlled trials: Importance, indications, and interpretation. Lancet 365:176-186, 2005.
11. Lagakos SW: The challenge of subgroup analyses-reporting without distorting. N Engl J Med 354:1667-1669, 2006.
12. Gardner MJ, Altman DG: Confidence intervals rather than p-values: Estimation rather than hypothesis testing. Br Med J 292:746-750, 1986.
13. Pignon JP, Ducreux M, Rougier PH: More patients needed in stage II colon cancer trials (letter). J Clin Oncol 18:235, 2000.
14. Pignon JP, Burdett S: Comment on "Survival improvement in resectable non-small cell lung cancer with (neo) adjuvant chemotherapy: Results of a meta-analysis of the literature" by T. Berghmans et al (letter). Lung Cancer 51:261-262, 2006.
15. Sekine I, Takad M, Nokihara H, et al: Knowledge of efficacy of treatment in lung cancer is not enough, their clinical effectiveness should also be know. J Thoracic Oncol 1:398-402, 2006.
16. Pignon JP, Hill C: Meta-analyses of randomised clinical trials in oncology. Lancet Oncol 2:475-482, 2001.
17. Piedbois P, Buyse M: Meta-analyses based on abstracted data: A step in the right direction, but only a first step. J Clin Oncol 22:3839-3841, 2004.
18. Tsao MS, Sakurada A, Cutz JC, et al: Erlotinib in lung cancer-molecular and clinical predictors of outcome. N Engl J Med 353:133-144, 2005.
19. HirschFR , Varella-Garcia M, PA Jr, et al: Molecular predictors of outcome with gefitinib in a phase III placebo-controlled study in advanced non-small-cell lung cancer. J Clin Oncol 24:5034-5042, 2006.
20. Burdett S, Stewart LA, Rydzewska LA: Systematic review and meta-analysis of the literature: Chemotherapy and surgery versus surgery alone in non-small cell lung cancer. J Thorac Oncol 1:611-621, 2006.
21. Lally BE, Zelterman D, Colasanto JM, et al: Postoperative radiotherapy for stage II or III non-small-cell lung cancer using the Surveillance, Epidemiology, and End Results database. J Clin Oncol 24:2998-3006, 2006.
22. Clark GM, Zborowski DM, Culbertson JL, et al: Clinical utility of epidermal growth factor receptor expression for selecting patients with advanced non-small cell lung cancer for treatment with erlotinib. J Thorac Oncol 1:837-846, 2006.
23. Michiels S, Koscielny S, Hill C: Prediction of cancer outcome with microarrays: A multiple random validation strategy. Lancet 365:488-492, 2005.
24. Paik S: Molecular profiling of breast cancer. Curr Opin Obstet Gynecol 18:59-63, 2006.
25. Olaussen K, 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 355:983-991, 2006.
26. Postoperative radiotherapy in non-small-cell lung cancer: Systematic review and meta-analysis of individual patient data from nine randomised controlled trials. PORT Meta-analysis Trialists Group. Lancet 352:257-263, 1998.
27. Liu BQ, Peto R, Chen ZM, et al: Emerging tobacco hazards in China: 1. Retrospective proportional mortality study of one million deaths. BMJ 317:1411-1422, 1998.