Adjuvant and Neoadjuvant Therapy of NSCLC

For patients with operable non-small cell lung cancer (NSCLC), surgery has long been the standard of care. However, despite complete resection, 5-year survival rates have been disappointing with about 50% of patients eventually suffering relapse and death from disease. Efforts at improving survival for patients with operable NSCLC have examined the addition of chemotherapy and/or radiation in the preoperative (neoadjuvant or induction) and postoperative (adjuvant) settings. Thoracic radiation when given after surgery has led to a reduction in local recurrence but has not improved overall survival. A postoperative radiotherapy (PORT) meta-analysis published in 1998 raised significant concerns about the potential hazards of PORT. More recent retrospective studies of PORT have found it safe and not associated with excessive deaths from intercurrent disease. Postoperative radiation is not recommended for completely resected stage I and II NSCLC patients, and its use should be individualized in patients with stage III disease. PORT is currently recommended only for patients at high risk of local relapse (extensive nodal involvement or positive surgical margin). Early trials of postoperative chemotherapy failed to demonstrate a consistent benefit. These trials suffered from poor design with heterogeneous patient populations, inadequate trial size, and less active drug regimens. A meta-analysis examining the role of chemotherapy in NSCLC published in 1995 found a trend in favor of adjuvant cisplatin-based chemotherapy. These findings led to renewed interest in adjuvant chemotherapy for NSCLC, and larger trials with more active chemotherapy regimens were undertaken. Several of these trials have demonstrated a clear survival advantage for patients treated with cisplatin-based adjuvant therapy. Updated meta-analyses have confirmed the benefit of postoperative chemotherapy in NSCLC. Postoperative cisplatin-based chemotherapy is now the standard of care for completely resected stage II and III NSCLC patients with good performance status. Preoperative or induction chemotherapy trials were investigated prior to the positive adjuvant clinical trial data. Support for this concept came from improved survival seen in the locally advanced but inoperable NSCLC patients where chemotherapy administered prior to definitive chest radiation therapy had improved survival. Possible advantages of preoperative administration of chemotherapy include radiographic and pathologic tumor response assessment, earliest treatment of clinically undetectable micrometastatic disease, and improved compliance. Randomized trials in stage IIIA patients found a significant survival benefit but were small studies and their findings remain controversial. Randomized trials in earlier stages have supported the use of chemotherapy in operable NSCLC, but overall survival differences have not achieved statistical significance. Meta-analyses have found significant benefit for preoperative chemotherapy in operable NSCLC. At this time, stronger data exist in support of adjuvant chemotherapy in patients with operable NSCLC. Preoperative chemotherapy should only be administered in the clinical trial setting.