Preoperative chemotherapy followed by surgery compared with primary surgery in resectable stage I (except T1N0), II, and IIIa non-small-cell lung cancer. A randomized trial comparing perioperative chemotherapy and surgery with surgery alone in resectable stage IIIA non-small-cell lung cancer. A randomized trial of mitomycin/ifosfamide/cisplatin preoperative chemotherapy plus surgery versus surgery alone in stage IIIA non-small cell lung cancer. Failure of the perioperative PCV neoadjuvant polychemotherapy in resectable bronchogenic non-small cell carcinoma. Results from a randomized phase II trial.
To evaluate whether preoperative chemotherapy (PCT) could improve survival in resectable stage I (except T1N0), II, and IIIA non-small-cell lung cancer (NSCLC).
                A randomized trial compared PCT to primary surgery (PRS). PCT consisted of two cycles of mitomycin (6 mg/m(2), day 1), ifosfamide (1.5 g/m(2), days 1 to 3) and cisplatin (30 mg/m(2), days 1 to 3), and two additional postoperative cycles for responding patients. In both arms, patients with pT3 or pN2 disease received thoracic radiotherapy.
                Three hundred fifty-five eligible patients were randomized. Overall response to PCT was 64%. There were two preoperative toxic deaths. Postoperative mortality was 6.7% in the PCT arm and 4.5% in the PRS arm (P =.38). Median survival was 37 months (95% confidence interval [CI], 26.7 to 48.3) for PCT and 26.0 months (95% CI, 19.8 to 33.6) for PRS (P =.15). Survival differences between both arms increased from 3.8% (95% CI, 1.3% to 25.1%) at 1 year to 8.6% (95% CI, 2.64% to 24.4%) at 4 years. A quantitative interaction between N status and treatment was observed, with benefit confined to N0 to N1 disease (relative risk [RR], 0.68; 95% CI, 0.49 to 0.96; P =.027). After a nonsignificant excess of deaths during treatment, the effect of PCT was significantly favorable on survival (RR, 0.74; 95% CI, 0.56 to 0.99; P =.044). Disease-free survival time was significantly longer in the PCT arm (P =.033).
                Although impressive differences in median, 3-year, and 4-year survival were observed, they were not statistically significant, except for stage I and II disease. Patients with resectable stage IIIA non-small-cell lung cancer have a low survival rate following standard surgical treatment. Nonrandomized trials in which induction chemotherapy or a combination of chemotherapy and radiation prior to surgery were used to treat patients with regionally advanced primary cancers have suggested that survival is improved when compared with treatment by surgery alone.
                We performed a prospective, randomized study of patients with previously untreated, potentially resectable clinical stage IIIA non-small-cell lung cancer to compare the results of perioperative chemotherapy and surgery with those of surgery alone.
                This trial was designed to test the null hypothesis that the proportion of patients surviving 3 years is 12% for either treatment group against the alternate hypothesis that the 3-year survival rate would be 12% in the surgery alone group and 32% in the perioperative chemotherapy group. The estimated required sample size was 65 patients in each group. The trial was terminated at an early time according to the method of O'Brien and Fleming following a single unplanned interim analysis. The decision to terminate the trial was based on ethical considerations, the magnitude of the treatment effect, and the high degree of statistical significance attained. 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). For patients in the former group, tumor measurements were made before each course of chemotherapy and the clinical tumor response was evaluated after three cycles of chemotherapy; they then underwent surgical resection. 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.
                In this trial, the treatment strategy using perioperative chemotherapy and surgery was more effective than surgery alone.
                This clinical trial strengthens the validity of using perioperative chemotherapy in the management of patients with resectable stage IIIA non-small-cell lung cancer. Further investigation of the perioperative chemotherapy strategy in earlier stage lung cancer is warranted. The efficacy of surgery or radiotherapy as conventional treatment for stage IIIA non-small cell lung cancer (NSCLC) is limited. Recent studies have pointed out that preoperative chemotherapy may improve survival. To reconcile the two approaches, we undertook a multidisciplinary randomized trial to examine the possible synergism between preoperative chemotherapy and surgery in improved survival. Stage IIIA NSCLC patients were randomly assigned to receive either three preoperative courses of mitomycin/ifosfamide/cisplatin chemotherapy and surgery or surgery alone. The median survival was significantly greater in the chemotherapy plus surgery group than in the surgery group (26 months v 8 months; P < .001). However, the prognostic value of the mutated K-ras gene data presented awaits the analysis of larger sample populations. Similarly, the role of high-dose cisplatin in inducing higher pathologic complete remissions has to be corroborated in future randomized trials. In 1985, the authors began a phase II study to assess the PCV perioperative polychemotherapy (cisplatin 100 mg/m2, cyclophosphamide 600 mg/m2, vindesine 3 mg/m2) in patients with resectable bronchogenic non-small cell carcinoma. Patients were randomized to receive either two preoperative courses of PCV chemotherapy, surgery, and two postoperative courses of PCV chemotherapy (PCV group) or immediate surgery (surgery group). A staging procedure using the CT scan was performed before randomization and, additionally, before surgery in the PCV group. There were 26 randomized patients, 13 in each group. In the PCV group, 11 patients agreed to receive the two preoperative courses of chemotherapy. A response was observed in five patients (45%), and a progression was observed in four patients (36%) leading to a cancellation of surgery in two of them. Postoperative care was the same for each group. Although no death could be related to chemotherapy, it was decided to stop entering new patients into this trial because of the rate of preoperative progression in the PCV group.
This analysis shows a significant increase in survival attributable to pre-operative chemotherapy. This is currently the best estimate of the effectiveness of this therapy, but is based on a small number of trials and patients. This analysis was unable to address important questions such as whether particular types of patients may benefit more or less from pre-operative chemotherapy or whether the early stopping of a number of included RCTs impacted on the results. These issues may be addressed by an ongoing individual patient data (IPD) meta-analysis.