The classic paper by Rosell et al addresses one of the more vexing issues in the treatment of lung cancer patients (ranking among many); the management of stage III disease in non-small cell lung cancer. In part, the controversy exists because many retrospective publications and small randomized trials have addressed a wide range of stage III subsets with inconsistent pathologic documentation of the nodal status. However, the critical question differs for two distinct groups within stage III patients:
1. In the group with minimal, nonbulky disease, initial surgical resection has been the standard of care. These subsets include T3N0 or N1, and non-enlarged N2 on CT scan. The debate here is whether preoperative chemotherapy with or without radiation therapy improves survival over surgery alone.
2. For the group with bulky disease, chemoradiation is the current standard of care. These tumors include bulky N2 disease on CT scan, N3 disease, and T4 primaries. The debate in this group is whether surgical resection after induction chemoradiotherapy improves outcome over chemoradiation alone.
The Rosell et al paper falls into the former group.
The study design
The study was a randomized phase III trial of stage IIIA non-small cell lung cancer patients
A surgery alone arm
An induction chemotherapy (chemotherapy plus surgery) arm where patients received three courses of mitomycin (6mg/m2), ifosfamide (3 g/m2), and cisplatin (50 mg/m2) given at three week intervals followed by surgery
All patients had radiation therapy after surgery and were treated to a total dose of 50 Gy
The primary objective was to determine whether preoperative chemotherapy would improve the five-year overall survival of stage IIIA patients which is estimated to be about 9 percent
All patients underwent bronchoscopy and all had high-performance status 70 or higher, with good lung function
Mediastinoscopy or mediastinotomy was carried out only if N2 disease was detected on CT scan
There was upfront stratification by previously proven predictive factors from other studies such as size of tumor, location of tumor, age, and N2 status
63 patients were enrolled and 60 were eligible; there were 30 patients randomized to each arm
There were no significant differences between the two groups in patient characteristics
However, 25 of 30 patients in the chemotherapy (83%) had mediastinoscopy. Whereas 19 of 30 patients (63%) in the surgery alone arm had mediastinoscopy
The overall response rate was 60 percent; (7%) or two patients had complete response
The median period of survival was 26 months in the patients treated with chemotherapy plus surgery, as compared with 8 months in the patients treated with surgery alone (P < 0.001)
The median period of disease-free survival was 20 months in the patients treated with chemotherapy plus surgery, as compared with 5 months in the surgery group (P < 0.001)
The risk of death was five times greater in the surgery group than in the chemotherapy plus surgery group
The rate of recurrence was 56 percent in the group treated with chemotherapy plus surgery and 74 percent in the group treated with surgery alone.
The chemotherapy plus surgery patients failed more locally versus the surgery alone patients who failed more with distant metastasis
This phase III trial addressing the effects of preoperative chemotherapy on the survival of patients with stage IIIA non-small cell lug cancer shows that preoperative chemotherapy increased the median survival of these patients.
As noted earlier, this strongly positive trial in favor of induction chemotherapy has generated much discussion and debate. One must consider when reviewing the Rosell et. al. trial that only 60 patients were a enrolled. We know that N2 disease was not required for eligibility and mediastinoscopy was not mandated if the mediastinum was negative on CT scan. In the study, 25 of 30 patients in the chemotherapy arm (83%) had mediastinoscopy, whereas only 19 of 30 patients (63%) in the surgery alone arm had mediastinoscopy. This leaves open the question of under staging of the surgery alone patients. One also wonders why the surgery arm did so poorly in this trial; despite the fact that 37% of them had N0 or N1 disease. This trial closed early due to the marked survival differences noted. However, it is not clear whether the early stopping rules for this very small trial accounted for the strong potential influence of even slight imbalances in substage or molecular prognosis between the arms.