Compared with patients who underwent treatment with chemotherapy plus radiotherapy (without surgery), there was no improvement in overall survival. However, an exploratory analysis of the data showed that surgery could improve overall survival, but only if a lobectomy was performed.
These results give "clear arguments in favor of surgery in well-selected subsets of patients," note Wilfried Eberhardt, MD, and colleagues from University Hospital Essen in Germany, in an accompanying editorial.
Expert thoracic centers have been routinely adding surgery to the management of selected patients with stage III disease after induction chemotherapy and chemoradiotherapy for a number of years, despite a lack of supporting evidence from randomized trials, the editorialists write.
Dr. Eberhardt and colleagues ask if surgery should now be performed in patients with stage IIIA(N2) NSCLC after induction chemoradiotherapy. They answer yes, but add that it should be a less extensive resection (e.g., lobectomy) than a pneumonectomy.
Benefit Seen Only in Subgroup of Patients
The study, led by Kathy Albain, MD, professor of medicine at Loyola University Chicago in Maywood, Illinois, found a benefit from surgery only in a subgroup of patients.
There was no overall survival benefit for patients who received surgery in addition to chemotherapy and radiation, compared with those who did not (23.6 months vs 22.2 months, hazard ratio [HR], 0.87; P = .24).
However, patients in the surgical group did experience improved median progression-free survival, compared with the nonsurgical group (12.8 months vs 10.5 months; HR, 0.77). At 5 years, 32 of the 202 patients (22%) in the surgical group remained free of disease, as did 13 of 194 patients (11%) in the nonsurgical group.
At 5 years, the researchers noted an absolute survival difference of 7% in favor of the surgical group; 37 of the patients (27%) remained alive, compared with 24 (20%) in the nonsurgical group, but this did not achieve statistical significance.
One reason for the absence of benefit with surgery, they surmised, might be related to the high death rate after pneumonectomy, which was primarily attributable to acute respiratory distress syndrome and other respiratory-related causes. An overall-survival matching analysis was feasible for 90 of 98 lobectomies and 51 of 54 pneumonectomies. The median overall survival with lobectomy was 33.6 months and without surgery was 21.7 months. At 5 years, 21 of 90 patients (36%) who had undergone lobectomy were alive, compared with 10 of 90 patients (18%) who had not.
Conversely, survival rates were nonsignificantly worse for pneumonectomy patients than for nonsurgical patients (18.9 months vs 29.4 months). At 5 years, overall survival rates were 22% with pneumonectomy and 24% without surgery.
It is unlikely that a prospective trial is going to be conducted to validate whether surgical approaches are better than nonsurgical approaches if lobectomies can be done, the authors note.
"Thus, medically healthy patients with stage IIIA(N2) nonsmall-cell lung cancer should be assessed by a team skilled in multimodality treatment, and treatment options can be considered during assessment," they write. "On the basis of the findings of our study, patients should be counseled about the risks and potential benefits of definitive chemotherapy plus radiotherapy with and without a surgical resection (preferably by lobectomy)."
Mixed Results From Previous Trials
Previous trials have produced mixed results. The results of several phase 2 pilot studies that were conducted to evaluate the role of surgical resection after induction treatment with chemotherapy alone or with concurrent chemotherapy plus radiotherapy proved controversial (J Clin Oncol. 2005;23:3257-3269; Lung Cancer. 2003;42;S9-S14; Pass HI et al. Lung cancer: principles and practice, 3rd ed. JB Lippincott Williams and Wilkins, 2005:626-649). Long-term survival rates were higher than anticipated, but substantial toxicity, postoperative morbidity, and mortality were observed, write the authors of the current study. These findings were also criticized because the patients had heterogeneous substages of disease and appeared to be unusually healthy, compared with the general population with stage III NSCLC.
As previously reported by Medscape Oncology, the European Organisation for Research and Treatment of Cancer (EORTC) conducted a phase 3 trial in which patients with stage IIIA(N2) NSCLC were randomized to surgery or radiotherapy after response to induction chemotherapy. The results showed little difference in survival between the 2 strategies.
In the multicenter phase 3 study by Dr. Albain and colleagues, patients with stage T1-3pN2M0 NSCLC received concurrent induction chemotherapy consisting of 2 cycles of cisplatin 50 mg/m2 on days 1, 8, 29, and 36, and etoposide 50 mg/m2 on days 1–5 and 29–33, plus radiotherapy (45 Gy). If there was no disease progression, patients were randomized to surgical resection or continued radiotherapy to a maximum dose of 61 Gy, followed by additional chemotherapy.
The editorialists emphasize that "further data from randomized trials are urgently needed to define the best selection criteria for bimodal or trimodal treatment."
The study was funded by National Cancer Institute, the Canadian Cancer Society, and the National Cancer Institute of Canada. The authors and the editorialists have disclosed no relevant financial relationships.
Lancet. Published online before print July 24, 2009. Abstract
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