Radiotherapy and chemotherapy in locally advanced non-small cell lung cancer: preclinical and early clinical data

Abstract

Over the past 20 years, combined treatment with radiotherapy and second-generation chemotherapy drugs was extensively studied in patients with locally advanced NSCLC and became the standard over radiotherapy alone in patients with good performance status. Radiosensitizing properties of cisplatin have been identified in the laboratory. Close temporal administration of cisplatin and radiation is mandatory for enhanced antitumor efficacy, but results in significant toxicity to normal tissues. Early clinical studies demonstrated that the concurrent administration of cisplatin during STD-RT was feasible, with acceptable esophageal toxicity, and had the potential of significantly improving locoregional control. Carboplatin administered concurrently with accelerated HFX-RT was responsible for a higher rate of esophageal toxicity. Further improvement in survival also requires an effective treatment of micro-metastatic disease through full-dose delivery of cytotoxic drugs and the addition of at least one more active drug in conjunction with cisplatin and radiotherapy to further improve locoregional control of the disease. In most clinical studies, etoposide was the second drug of choice because of its own radiosensitizing properties and possible synergy with cisplatin. In numerous phase II studies, concurrent radiotherapy and PE resulted in reproducible results in terms of local control (30%-40%), median survival (15-18 months), survival at 2 years (35%-40%), and survival at 5 years (25%-30%). In phase III studies, these results were shown to be superior to radiotherapy alone and to induction chemotherapy followed by STD-RT. The question of the potential benefit of HFX-RT combined with PE has been addressed in phase II and III studies. At this time, there is no firm evidence that concurrent chemotherapy with HFX-RT is superior to concurrent chemotherapy with STD-RT in terms of local control and survival. Only a significant benefit in terms of local control or survival would justify the significant increase of esophageal toxicity observed with HFX-RT, which remains the main limiting factor of concurrent chemoradiotherapy with PE. Studies on postinduction surgery after concurrent chemoradiotherapy have been of major interest, demonstrating that a complete pathologic response rate of 25% to 30% could be achieved with a relatively low dose of radiation (45 Gy) and that downstaging was a major determinant for improved long-term survival. Long-term survival after trimodality treatment, however, does not appear to be significantly different from what can be achieved with concurrent chemoradiotherapy alone in phase II studies. Whether postinduction surgery is beneficial to patients with histologically proved stage III (N2) and stage IIIB patients was the question addressed in a large, recently completed phase III intergroup trial and of which the results are eagerly awaited. Over the past 10 years, further progress in radiation technology has been accomplished through three-dimensional treatment planning, multileaf collimators, and electronic portal imaging devices, leading to high-precision conformal radiotherapy and dose escalation and (it is hoped) to improved local control. Intensity-modulated radiotherapy and respiratory gating remain to be evaluated. Accurate delineation of critical organs and pretreatment analysis of toxicity-predicting factors allow for better protection of normal intrathoracic tissues such as lung and esophagus and, it is hoped, will lead to a significant reduction in the incidence of radiation esophagitis and pneumonitis. Third-generation drugs such as taxanes, vinorelbine, and gemcitabine have demonstrated high response rates in NSCLC patients with favorable toxicity profiles. These drugs have also shown major radiosensitizing properties in the laboratory and in the clinical setting, often leading, however, to excessive radiosensitization and unacceptable normal tissue toxicities when administered at full dose concurrently with radiotherapy. Weekly administration of these drugs at reduced doses during a full course of conformational radiotherapy up to 70 Gy or more, however, resulted in encouraging results in several phase II studies, with median survival in excess of 20 months and 2- and 3-year survival rates near 50% and 40%, respectively. The respective benefits of either induction or consolidation full-dose chemotherapy with these drugs, before or after concurrent chemoradiotherapy with second- or third-generation chemotherapy, are presently being evaluated in phase III studies. As a result of improved survival and enhanced local control, most of these studies show a significant increase in the incidence of brain metastases. Because the brain is often the first site of relapse after concurrent chemoradiotherapy with or without surgery, the issue of prophylactic cranial irradiation is currently being addressed in a phase III trial.