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Adjuvant Treatment of Non-Small-Cell Lung Cancer: How Do We Improve the Cure Rates Further?

Adjuvant Treatment of Non-Small-Cell Lung Cancer: How Do We Improve the Cure Rates Further?

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.

Lung cancer remains the leading cause of cancer deaths in the United States. Surgery is still the standard of care for the treatment of early-stage non-small-cell lung cancer (NSCLC). Unfortunately, only about one-third of patients present with disease that is potentially resectable. Patient outcome is closely linked to pathologic stage; therefore, it is of utmost importance that thorough intraoperative staging be performed, including adequate lymph node sampling. Surgery, however, is an imperfect therapy and 5-year survival rates have been disappointing because of distant and local recurrences (Table 1).[1] Approximately 90% of disease recurrences after surgery present in the form of distant metastases, which are most often the cause of patient mortality.

Adjuvant chemotherapy after surgical resection would appear to be the logical approach to reducing disease recurrence and improving survival. Early adjuvant trials did not support the routine administration of postoperative chemotherapy. A meta-analysis published in 1995 examined the results of randomized trials of surgery compared with surgery plus chemotherapy conducted between 1965 and 1991.[2] Treatment with cisplatin-based chemotherapy resulted in a hazard ratio (HR) of 0.87 (P = .08) with a 13% reduction in death favoring adjuvant therapy. Although this analysis did not make postoperative therapy the standard of care, it led to a renewed interest in pursuing adjuvant trials in early-stage NSCLC. Since the appearance of this meta-analysis, the results of several randomized clinical trials now support the use of adjuvant chemotherapy after surgical resection. This article will review the results of the more recent adjuvant trials and discuss the future direction of research in this area.

Early Adjuvant Trials

The need for postoperative adjuvant therapy was recognized early in the treatment of lung cancer. A number of trials were conducted in the 1960s and 1970s utilizing immunotherapy (bacillus Calmette-Gurin, or BCG), alkylating agents, and/or radiotherapy for the treatment of lung cancer after surgical resection. These studies were plagued by insufficient sample size, inadequate surgical staging, and inferior chemotherapy.

The Lung Cancer Study Group (LSCG) was founded in the late 1970s. Patients enrolled on the LCSG adjuvant trials underwent rigorous mediastinal lymph node sampling, which allowed for proper stratification and survival analysis. These studies[3-5] (Table 2) usually utilized CAP (cyclophosphamide, doxorubicin [Adriamycin], cisplatin [Platinol]) as the adjuvant chemotherapy. Frequently, such trials showed an improvement in disease-free survival and median survival for the patients who received adjuvant chemotherapy, but no significant improvement in overall survival was seen. Moreover, difficulty was encountered in delivering all the intended chemotherapy.

A study from Finland that also utilized CAP chemotherapy demonstrated significant improvements in disease-free survival and long-term survival (10-year survival: 61% vs 48%) favoring adjuvant treatment.[6] When the statistics were adjusted for imbalances among patient characteristics, however, the survival differences were no longer significant.

Despite the fact that no one trial among these early studies clearly supported the use of adjuvant chemotherapy, they collectively suggested that with larger patient sample sizes, uniform surgical staging, and adequate chemotherapy delivery, it would be possible to demonstrate an advantage for postoperative treatment.

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