A randomized trial comparing preoperative chemotherapy plus surgery with surgery alone in patients with non-small-cell lung cancer.
Rosell R et al.     N Engl J Med 1994 Jan 20;330(3):153-158
We studied 60 patients (59 men and 1 woman) with stage IIIA non-small-cell lung cancer. The patients were randomly assigned to receive either surgery alone or three courses of chemotherapy (6 mg of mitomycin per square meter of body-surface area, 3 g of ifosfamide per square meter, and 50 mg of cisplatin per square meter) given intravenously at three-week intervals and followed by surgery. All patients received mediastinal radiation after surgery. 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 former group, as compared with 5 months in the latter (P < 0.001). 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.

Surgical resection of stage IIIA and stage IIIB non-small-cell lung cancer after concurrent induction chemoradiotherapy. A Southwest Oncology Group trial.
Rusch VW et al.  J Thorac Cardiovasc Surg 1993 Jan;105(1):97-104
Eligible patients had pathologically documented T1-4 N2-3 disease (without pleural effusions). Induction therapy was cisplatin, 50 mg/m2, days 1, 8, 29, and 36 plus VP-16, 50 mg/m2, days 1 to 5, and 29 to 33 plus concurrent radiotherapy (4500 cGy, 180 cGy fractions). Resection was attempted 3 to 5 weeks after induction if the response was stable, partial, or complete. Sixty-eight of (91%) patients were eligible for operation, and 63 of 75 patients (84%) underwent thoracotomy. Fifty five of 75 patients (73%), including 12 of 16 with a stable response, had a complete resection. Four of 63 patients died postoperatively (6%). The 2-year survival is 40% for both stages IIIA and IIIB. Current survival is significantly better than survivorship among historical control patients and provides a firm basis for subsequent phase III clinical trials. 


A randomized trial comparing perioperative chemotherapy and surgery with surgery alone in resectable stage IIIA non-small-cell lung cancer.
Roth JA et al   J  Natl Cancer Inst 1994 May 4;86(9):673-680
In total, 60 patients were randomly assigned between 1987 and 1993 to receive either six cycles of perioperative chemotherapy (cyclophosphamide, etoposide, and cisplatin) and surgery (28 patients) or surgery alone (32 patients). Patients who had documented tumor regression after preoperative chemotherapy received three additional cycles of chemotherapy after surgery.  After three cycles of preoperative chemotherapy, the rate of clinical major response was 35%. Patients treated with perioperative chemotherapy and surgery had an estimated median survival of 64 months compared with 11 months for patients who had surgery alone (P < .008 by log-rank test; P < .018 by Wilcoxon test). The estimated 2- and 3-year survival rates were 60% and 56% for the perioperative chemotherapy patients and 25% and 15% for those who had surgery alone, respectively. 


Concurrent cisplatin/etoposide plus chest radiotherapy followed by surgery for stages IIIA (N2) and IIIB non-small-cell lung cancer: mature results of Southwest Oncology Group phase II study 8805.
Albain KS, et al.  J Clin Oncol 1995 Aug;13(8):1880-1892
Biopsy proof of either positive N2 nodes (IIIAN2) or of N3 nodes or T4 primary lesions (IIIB) was required. Induction was two cycles of cisplatin and etoposide plus concurrent chest RT to 45 Gy. Resection was attempted if response or stable disease occurred. A chemoRT boost was given if either unresectable disease or positive margins or nodes was found. RESULTS:  The objective response rate to induction was 59%, and 29% were stable. Resectability was 85% for the IIIA(N2) group eligible for surgery and 80% for the IIIB group. There was no survival difference (P = .81) between stage IIIA(N2) versus stage IIIB (median survivals, 13 and 17 months; 2-year survival rates, 37% and 39%; 3-year survival rates, 27% and 24%).

The role of multimodality therapy in locoregional non-small cell lung cancer.
Martini N et al.  Surg Oncol Clin N Am 1997 Oct;6(4):769-791
Surgical treatment is offered to all patients with stage I or II disease and to specific groups of patients with stage III or IV disease. Cisplatin based on regimens of induction chemotherapy or chemoradiotherapy have proven to be valuable in stage IIIA (N2) disease. We now recommend induction therapy on an investigational basis to most patients with stage I or II tumors and to all those with stage IIIA tumors, when the 5 year survival is anticipated to be less than 50% with conventional therapy. Many new chemotherapy agents effective in advanced stage lung cancer are currently integrated into this multimodality approach in hopes of further improvement in tumor control and survival. 


Postoperative radiation therapy in non-small cell lung cancer.
Emami B et al.   Am J Clin Oncol 1997 Oct;20(5):441-448
One hundred seventy-three patients with the diagnosis of non-small cell lung cancer (NSCLC) were treated with surgery and postoperative radiation therapy (RT) Locoregional control for stages I, II, and IIIA was 85, 75, and 85%, respectively. Five-year actuarial survival was 35% for stage I and 20% for stages II and IIIA. Patients with N0 disease (positive margins) had 5-year survival of 25%, whereas patients with N1 and N2 disease had a 5-year survival of 20%.

Postoperative radiotherapy in non-small-cell lung cancer: systematic review and meta-analysis of individual patient data from nine randomised controlled trials. PORT Meta-analysis Trialists Group.
Lancet 1998 Jul 25;352(9124):257-263 
Data on 2128 patients from nine randomised trials (published and unpublished) were analysed by intention to treat. There were 707 deaths among 1056 patients assigned postoperative radiotherapy and 661 among 1072 assigned surgery alone. The results show a significant adverse effect of postoperative radiotherapy on survival (hazard ratio 1.21 [95% CI 1.08-1.34]). This 21% relative increase in the risk of death is equivalent to an absolute detriment of 7% (3-11) at 2 years, reducing overall survival from 55% to 48%. Subgroup analyses suggest that this adverse effect was greatest for patients with stage I/II, N0-N1 disease, whereas for those with stage III, N2 disease there was no clear evidence of an adverse effect.


Effectiveness of postoperative irradiation in stage IIIA non-small cell lung cancer according to regression tree analyses of recurrence risks.
Sawyer TE, et al.    Ann Thorac Surg 1997 Nov;64(5):1402-1407
The use of adjuvant postoperative TRT (compared with operation alone) was associated with an improvement in freedom from local recurrence and survival for patients who had an intermediate or high risk of local recurrence and death. However, the greatest level of improvement in freedom from local recurrence (p < 0.0001) and survival (p = 0.0002) associated with the use of adjuvant postoperative TRT was in the high-risk group. Similarly, but of lesser magnitude, the intermediate-risk group had improved freedom from local recurrence and survival rates with the use of adjuvant post-operative TRT (p = 0.002 and p = 0.01, respectively). For the low-risk group, the freedom from local recurrence and survival rates were not statistically different between the patients who received adjuvant postoperative TRT and those who underwent observation.