Combined modality therapy of lung cancer

Abstract

Combined modality therapy for lung cancer was first demonstrated to be successful in limited-stage small cell lung cancer. Concurrent administration of chemotherapy with chest and elective brain irradiation appears to produce the best results, with cisplatin/etoposide as the core chemotherapy. Using such programs, 2-year survival in the 40% range and 5-year survivals in excess of 20% may be expected, based on the results of multiple studies. Attempts to improve on these results through the use of altered schemes of chest irradiation or the delivery of high-dose consolidation chemotherapy are ongoing but to date have not been shown to affect survival significantly. We remain at a plateau in the effectiveness of combined modality therapy for small cell lung cancer, with little evidence that it impacts survival at all in extensive-stage disease. The incorporation of new agents in combination chemotherapy regimens, more "specific" immunotherapy directed at tumor-associated antigens, and the potential adjunctive use of broad-spectrum neuropeptide antagonists offer promise for the future. In non-small cell lung cancer, the sequential use of platinum-based chemotherapy and chest irradiation appears superior in survival to standard, daily fractionated radiation therapy used alone, with long-term survival increased from 5-10% to 15-20%. Concurrent administration of chemotherapy with cisplatin/etoposide and chest irradiation produces 2-year survival in the range of 30%, about twice that would be expected for radiation therapy alone, but has not been compared to it in the setting of a randomized trial. Low-dose cisplatin on a daily basis has been combined as a "sensitizer" with chest irradiation, producing initial results that appeared encouraging. However, these have not been reproduced in subsequent, randomized trials. Another approach to combined modalities has been to give chemotherapy or chemotherapy/radiation therapy as induction, followed by surgical resection, with or without subsequent additional treatment. Most patients (80-85%) can be resected, with encouraging survival at 2 and 3 years in the Southwest Oncology Group experience (37 and 26%, respectively). However, toxicity is greater, and such an approach is associated with an overall mortality risk in the range of 10%. A current intergroup study attempts to define the role of surgery in this setting. The major recent development that is likely to influence the future of combined modality therapy for this disease is the advent of multiple new chemotherapeutic agents, such as the taxanes, gemcitabine, vinorelbine, and the topoisomerase-I inhibitors, which have activity in stage IV disease. The immediate challenge is how to combine these agents with platinum analogues, radiation, and surgery. Aiding this process may be the use of molecular biological "markers" that may predict the chance of success or failure with a given systemic agent. The next decade is likely to see substantial improvements in the outcome of treatment for patients with stages I-III non-small cell lung cancer, based on the systemic exploration of combined modalities.