Trimodality Therapy for Non–Small-Cell Lung Cancer

Introduction

The role of neodajuvant chemotherapy in the treatment of resectable stage IIIA non–small-cell lung cancer was established in several trials. Rosell et al randomly allocated 60 patients with stage IIIA non–small-cell lung cancer to receive either three cycles of chemotherapy followed by surgery and postoperative mediastinal radiotherapy, or surgery followed by radiotherapy.[1] At 3 years, there were no survivors in the surgery plus radiotherapy group, but 30% of patients in the group treated with neoadjuvant chemotherapy survived. The difference in median survival (26 vs 8 months) was highly significant (P < .001).

Pass et al randomized 27 patients to receive either preoperative chemotherapy, surgery, and postoperative chemotherapy or surgery and postoperative mediastinal irradiation.[2] A trend toward increased overall and median survival was observed in the group that received chemotherapy, but at the time of the report, it had not yet reached statistical significance (P = .095).

Finally, Roth et al studied a group of 60 patients who were staged with mediastinoscopy and allocated to receive either six cycles of perioperative chemotherapy and surgery or surgery alone.[3] The estimated 3-year survival rate was 56% in the neoadjuvant chemotherapy group compared to 15% for those who had surgery alone. In an update of the results after a median follow-up of 82 months, the survival increase in the perioperative chemotherapy group was maintained.[4] Taken together, these trials found roughly a 30% improvement in median survival when neoadjuvant chemotherapy was combined with surgery.

These findings are in striking contrast to those obtained with postoperative adjuvant chemotherapy. In general, chemotherapy given after surgery has resulted in no survival benefit at 5 years in most studies.[5-7] Some of these studies showed an increase in recurrence-free survival that did not manifest as a prolongation of overall survival. A few other studies showed a survival benefit, although it was of relatively small magnitude.[8,9] Because of persistent confusion about the benefits of postoperative chemotherapy, a large meta-analysis of all available randomized trials evaluating postoperative chemotherapy was conducted.[10] This analysis suggested that chemotherapy given after surgery provided a small benefit (approximately 5%) in long-term survival. In contrast, the three trials described above identified an average improvement of 30% in long-term survival when chemotherapy was administered before surgery.

However, not all prospective trials have found a survival advantage with the addition of neoadjuvant chemotherapy. The Cancer and Leukemia Group B (CALGB) began a phase II comparison of “best local-regional therapy” with or without neoadjuvant chemotherapy. A total of 47 patients were randomized between the two treatment arms. No difference in the rate of complete surgical resection, failure-free survival, nor overall survival was observed.[11] The study was ultimately closed because of an inability to accrue patients. Nonetheless, it is important to realize that the “standard” use of neoadjuvant chemotherapy is based on studies involving fewer than 150 patients.

The remainder of this article will evaluate the available data on the trimodality treatment of stage IIIA and IIIB non–small-cell lung cancer, as well as developing data on the neoadjuvant treatment of stage II lung cancer.

Surgery With or Without Radiotherapy for Stage IIIA Disease

Before revision of the International System for Staging Lung Cancer in 1997,[12] T3N0 lesions were considered stage IIIA non–small-cell lung cancer. This review will include only those results for patients with N2 disease. Table 1 summarizes the surgical results of representative large series of patients with N2 nodal involvement who underwent resection. Attention is drawn to the differences in survival for patients with radiographic or clinically evident nodal involvement as opposed to lesser nodal involvement identified only at surgery.

Martini and colleagues from Memorial Sloan-Kettering Cancer Center (MSKCC, New York, NY) have collected the most extensive data.[13] Their group operated on 404 patients with N2 disease, defined by either radiographic or pathologic criteria (these patients rarely had mediastinoscopy). Most of their patients also received postoperative radiotherapy. Overall, the 5-year survival rate was 30%. For patients with radiographically detectable N2 disease, the 5-year survival rate was only 9%.

In contrast to MSKCC, Pearson and colleagues from Toronto performed mediastinoscopy on 141 patients and demonstrated N2 nodal disease.[14] For patients who had enlarged nodes visible on chest x-ray and underwent resection, the survival rate at 5 years was 9%. The survival rate was 24% after surgery in patients whose mediastinal nodes were found to be involved at mediastinoscopy or at resection. In another study, Mountain found 5-year survival rates of 39% for patients with N2 squamous cell carcinoma and 14% for patients with N2 adenocarcinoma who had resection.[15] Most series show long-term survival between 8% and 20% in patients who successfully undergo surgical resection.[16]

Surgical Resection and Radiotherapy for N2 Disease

Adding radiotherapy, either adjuvant or neoadjuvant, to surgery adds little to the results observed with surgery alone. In a large Veteran’s Administration study, radiotherapy given after surgery actually decreased long-term survival.[17] Kirsh et al found 5-year survival rates of 30% for squamous cell carcinoma and 13% for adenocarcinoma in patients who were resected and treated with postoperative radiotherapy.[18] Warram studied preoperative radiotherapy, treating patients with radiographically involved mediastinal nodes with radiotherapy and then randomizing them to surgery or observation.[19] Survival at 5 years was 8% for the resected group and 6% for the radiotherapy-alone group.

In another study, patients who were resected and received postoperative radiotherapy had a survival rate at 5 years of 11%.[20] At the Dana Farber Cancer Institute (Boston, MA), Sherman et al found a 5-year survival rate of 18% when patients received preoperative irradiation followed by thoracotomy.[21] The survival rate of all resectable patients was 27%. Hilaris et al obtained a 5-year survival rate of 22% by combining aggressive resection with intraoperative brachytherapy and postoperative external radiotherapy.[22] Finally, a recent large meta-analysis of randomized trials evaluating postoperative radiotherapy found a 21% increase in the relative risk of dying that was greatest for patients with N0 or N1 disease.[23] There was no demonstrable benefit of postoperative radiotherapy for patients with stage IIIA non–small-cell lung cancer, including those with N2 disease.

Chemotherapy and Radiotherapy in Unresectable Stage III Disease

While the role of chemotherapy in stage IV non–small-cell lung cancer has only recently been established, the combination of chemotherapy and radiotherapy has an established role in the treatment of unresectable stage III disease based on the results of large randomized studies (Table 2). Fram et al studied six cycles of CAP (cyclophosphamide, doxorubicin(Drug information on doxorubicin) [Adriamycin], and cisplatin(Drug information on cisplatin) [Platinol]) chemotherapy and 57 Gy radiation in patients with histologically proven N2 disease.[24] The group found a response rate of 66% and a median survival of 9 months; there were no 5-year survivors. Dillman et al for CALGB reported a significant improvement in long-term survival when patients with stage IIIA disease were treated with the combination of chemotherapy (cisplatin and vinblastine(Drug information on vinblastine) [Velban]) and radiotherapy (60 Gy) compared with radiotherapy alone.[25] Median survival improved from 9.6 to 13.7 months (P = .012) and the 5-year survival rate improved from 6% to 17% with the combination of chemotherapy and radiotherapy.[26]

These data were confirmed in subsequent studies.[27-29] Thus, combined- modality therapy, whether sequential chemotherapy and radiotherapy or concurrent radiotherapy and radiosensitizing chemotherapy, is now the standard of care for patients with unresectable stage III non–small-cell lung cancer, yielding 3-year survival rates between 0% and 23%.