Surgery remains the initial treatment for patients with early-stage non-small-cell lung cancer (NSCLC). Additional therapy is necessary because of high rates of distant and local disease recurrence after surgical resection. Early trials of adjuvant chemotherapy and postoperative radiation were often plagued by small patient sample size, inadequate surgical staging, and ineffective or antiquated treatment. A 1995 meta-analysis found a nonsignificant reduction in risk of death for postoperative cisplatin-based chemotherapy. Since then, a new generation of randomized phase III trials have been conducted, some of which have reported a benefit for chemotherapy in the adjuvant setting. The role of postoperative radiation therapy remains to be defined. It may not be beneficial in early-stage NSCLC but still may have utility in stage IIIA disease. Improvement in survival outcomes from adjuvant treatment are likely to result from the evaluation of novel agents, identification of tumor markers predictive of disease relapse, and definition of factors that determine sensitivity to therapeutic agents. Some of the molecularly targeted agents such as the angiogenesis and epidermal growth factor receptor inhibitors are being incorporated into clinical trials. Preliminary results with gene-expression profiles and lung cancer proteomics have been promising. These techniques may be used to create prediction models to identify patients at risk for disease relapse. Molecular markers such as ERCC1 may determine response to treatment. All of these innovations will hopefully increase cure rates for lung cancer patients by maximizing the efficacy of adjuvant therapy.
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.
Meanwhile the development of molecular prognostic models, an area that many (including our group) have labored in, continues to evolve. Immunohistochemical and mRNA assays, genomic, and proteomic approaches have all been developed in the past decade. One awaits the emergence of prospective validations of these different approaches, and ultimately, the development of an integrated approach incorporating the molecular prognosis, and individualized treatment of patients with operable lung cancer.
Controversies Surrounding Stage of Disease and Use of Radiation Therapy
From a practical approach, two aspects that have been thrown into question in the past decade are the roles of radiation oncology in the postoperative setting and the appropriate stages for which chemotherapy and radiotherapy can be employed. As the authors note, the consensus at this time is that radiation treatment is appropriate for patients with mediastinal nodal disease. They encourage radiation as a treatment in patients with multistation disease and/or extracapsular spread, based on the data available. In terms of stage, many physicians currently shy away from treating patients with stage IB disease, while the treatment of stage II and IIIA NSCLC with adjuvant chemotherapy is prevalent. The CALGB study and others have left insights into a possible role for chemotherapy in patients with larger (> 4 cm) and more aggressive stage IB tumors, but this has not been resolved definitively.
In conclusion, this well-crafted discussion by Drs. Wozniak and Gadgeel describes state-of-the-art treatment of operable lung cancer and addresses many of the current controversies surrounding adjuvant and induction chemotherapy, placing them into a timely and thoughtful perspective. While their unbiased look shows how far the field has come in the past decade-and many prefer to look at the glass as perhaps one-quarter full today-the abysmal survival of patients with lung cancer mandates the support of high-quality translational clinical research in lung cancer for the immediate and foreseeable future.
-Fadlo R. Khuri, MD
The author has no significant financial interest or other relationship with the manufacturers of any products or providers of any service mentioned in this article.
Bacillus Calmette-GuÃ©rin (BCG)