In their review of recent advances in the adjuvant treatment of non-small-cell lung cancer (NSCLC), Drs. Wozniak and Gadgeel carefully cover the distance traversed by investigators over the past 2 decades before arriving at current state-of-the-art treatment—that is, the administraton of chemotherapy for selected patients with locally advanced lung cancer in an attempt to enhance their survival. The authors discuss the limitations of the early studies, which, whether due to patient heterogeneity, small sample size, or the modestly effective agents employed, failed to show a survival benefit. In the modern era, third-generation cisplatin-based chemotherapy has been found to improve median survival in patients with resectable stage II/IIIA NSCLC. The authors also review the somewhat more ambiguous evidence regarding radiation therapy. They properly place into perspective the lack of adequately powered data to resolve the current dilemma of timing of chemotherapy in operable lung cancer—ie, whether to proceed with induction (or neoadjuvant therapy) vs the better established adjuvant-approach.
Drs. Wozniak and Gadgeel conclude by discussing the incorporation of novel targeted therapeutic approaches to lung cancer, focusing on the best-studied areas: targeting angiogenesis and the epidermal growth factor receptor (EGFR). They also carefully review the data that have emerged over the past few years on primary tumor factors prognostic for cancer relapse and those predictive of response to chemotherapy. The authors maintain a balanced approach to an often contentious body of literature, emerging with clear recommendations. Nonetheless, it is worth reviewing some of the more controversial areas, even as we find ourselves in an era of relative consensus among lung cancer investigators. The areas we will discuss are the adjuvant vs induction chemotherapy debate, debates surrounding the role of radiation therapy and the stages of disease that may benefit from different modalities, incorporation of novel agents, and the role of molecular prognostic factors in lung cancer treatment.
Adjuvant vs Neoadjuvant
As of 2006, the momentum has swung squarely in favor of adjuvant chemotherapy. The early, pilot induction trials were strikingly positive, but time has attenuated the excitement that these small studies generated. The failure of Southwest Oncology Group (SWOG)-9900 to accrue in a timely fashion further blunted the excitement for induction or neoadjuvant chemotherapy. Meanwhile, four out of the last five adequately powered trials (the International Adjuvant Lung Cancer Trial [IALT], JBR.10, the Adjuvant Navelbine International Trialist Association [ANITA] trial, and the uracil/tegafur [UFT] trial) have all shown survival advantages in favor of cisplatin-based adjuvant chemotherapy, which has emerged as the new standard.[3-6]
Controversy continues to shroud the Cancer and Leukemia Group B (CALGB) study, which targeted stage IB patients with a carboplatin rather than a cisplatin-based approach, and whose results are no longer definitive. Physicians now await the results of the Neoadjuvant Taxol/Carboplatin Hope (NATCH), a three-armed trial that may well tip the balance toward a combination platinum-taxane approach in the induction setting, if the positive trends first discussed by Dr. Rosell continue to hold true.
Incorporation of Novel Agents
Based on positive phase III data in advanced disease, a national trial testing bevacizumab (Avastin) in the adjuvant setting has emerged. This well-designed, large trial adding bevacizumab to cisplatin-based chemotherapy (the second-agent choices are docetaxel, vinorelbine, and gemcitabine [Gemzar]), represents the consensus of the US cancer cooperative groups. As the authors thoughtfully reflect, there continues to be significant anxiety about the incorporation of bevacizumab in this setting in potentially curable patients, given the occasional fatal toxicities seen in Eastern Cooperative Oncology Group (ECOG)-4599.
Meanwhile, the negative results of SWOG-0023, with an increasingly inferior survival associated with the addition of gefitinib (Iressa) in sequence following chemoradiation and docetaxel, has significantly diminished the interest of investigators in giving EGFR tyrosine kinase inhibitors (TKI) in this setting. Nonetheless, a phase III adjuvant trial of erlotinib (Tarceva), the US Food and Drug Administration (FDA)-approved EGFR TKI, is being launched in the adjuvant setting after patients complete chemotherapy for early to intermediate-stage lung cancer.
Molecular Prognostic Factors of Survival and Predictors of Sensitivity to Chemotherapy
The authors carefully describe recent publications and the consensus that has developed on the role of DNA repair pathways in predicting sensitivity to cisplatin. The nucleotide-excision repair complex has been well explored by the several groups, and a recent assessment of the IALT population makes a case for ERCC1 as both a predictor of response to cisplatin-based chemotherapy and a favorable prognostic indicator for patients with operable lung cancer. As the authors cautiously note, we await prospective phase III validation of these results before their incorporation into standard care.
Bacillus Calmette-Guérin (BCG)