Preoperative Chemotherapy Does Not Increase Survival in Patients with Non–Small-Cell Lung Cancer
Roxanne Nelson

June 15, 2007 — Preoperative chemotherapy for non–small-cell lung cancer (NSCLC) has been used in an attempt to improve survival, but the largest randomized trial to date has not found a survival benefit in patients with operable NSCLC. The results, which were presented at American Society of Clinical Oncology 43rd Annual Meeting in Chicago and published online June 3 in Lancet Oncology, found that neoadjuvant chemotherapy did not appear to affect patterns of local recurrence and distant progression in patients who had undergone a complete resection. It also did not seem to affect overall survival in patients who had an incomplete resection.
In an accompanying editorial, Frances Shepherd, MD, and Penelope Bradbury, MD, from the University Health Network, Princess Margaret Hospital and the University of Toronto, in Ontario, point out that trials of postoperative chemotherapy in this population were consistently accompanied by high toxicity and poor compliance. Results from small phase 2 suggested that compliance might be better if chemotherapy were given before surgical resection and that there was a survival advantage when administered preoperatively.
The role of neoadjuvant chemotherapy in NSCLC remained undefined, as some studies found a benefit while others did not. The editorialists write "2 trials of postoperative chemotherapy and a meta-analysis in 4584 patients have shown convincingly that adjuvant chemotherapy results in a statistically significant and clinically meaningful survival advantage for patients with completely resected NSCLC." Thus, postoperative chemotherapy has become the worldwide standard after completing resection, although there are still strong proponents for both the preoperative and postoperative viewpoints.
Lead investigator Richard Stephens, MD, from the Medical Research Council Clinical Trials Unit, in London, United Kingdom, and colleagues randomized a total of 519 patients with NSCLC from 70 centers to receive neoadjuvant chemotherapy and surgery or surgery only. The chemotherapy protocol was selected from a list of standard regimens, and the primary outcome measure was overall survival, analyzed on an intention-to-treat basis.
The majority of patients (61%) had clinical stage I disease, with 31% having stage II and 7% stage III. Of the group who received neoadjuvant chemotherapy, 75% completed all 3 cycles, and the researchers observed that a partial or complete response was achieved in 49% of the patients who received chemotherapy.
The use of neoadjuvant chemotherapy appeared to improve a number of symptoms that had been reported at baseline. A comparison of prechemotherapy clinical staging and surgical pathological staging showed that 59% of the group receiving surgery only and 61% of the patients receiving chemotherapy had their initial staging revised. A larger percentage (31%) in the chemotherapy group experienced downgrades in their clinical staging, as compared with the surgery-only group (18%).
A small percentage of patients (about 5%) who received neoadjuvant chemotherapy were able to undergo a lobectomy rather than a pneumonectomy, and their rate of postoperative complications was similar to that of the other group. The use of chemotherapy also did not appear to impair quality of life. However, neoadjuvant chemotherapy did not provide a benefit in terms of overall survival. The median and 5-year survival rate was estimated to be 55 months and 45% for patients in the surgery-only group, and 54 months and 44% for those who received chemotherapy.
"Combining this result with all the other randomized trials of neoadjuvant chemotherapy suggests a relative benefit of 12% for neoadjuvant chemotherapy, equivalent to an absolute survival benefit of 5% at 5 years," the authors write.
This is the largest randomized trial of neoadjuvant chemotherapy in operable NSCLC that has been reported until now, they conclude, "and on its own shows no evidence of an overall survival benefit for neoadjuvant chemotherapy."
The trial was funded by the British Medical Research Council, and Lilly gave an unrestricted educational grant to the European Organization for Research and Treatment of Cancer and the Nederlandse Vereniging van Artsen voor Longziekten en Tuberculose.
Lancet Oncol. 2007. Published online June 3, 2007.
American Society of Clinical Oncology 43rd Annual Meeting: Abstract 7518. Presented June 3, 2007.

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