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Postoperative and Preoperative Chemotherapy for Non-Small-Cell Lung Cancer

Philip Bonomi, MD, and L. Penfield Faber, MD

A review of comparative trials and meta-analyses suggests a benefit from preoperative therapy and postoperative adjuvant treatment for patients with non-small-cell lung cancer.

Background: Few randomized trials of preoperative and postoperative adjuvant systemic therapy have been performed in patients with non-small-cell lung cancer (NSCLC).
Methods: The authors reviewed the recent literature on comparative trials and meta-analyses to determine the current status of adjuvant therapy for patients with NSCLC.
Results: Postoperative adjuvant therapy with cisplatin-containing regimens reduces the risk of death by 3% at two years and by 5% at five years. Preoperative therapy can clear tumor in the resected specimen in approximately 15% of cases, and two small trials report substantial survival benefit.
Conclusions: The development of new and more active regimens for NSCLC may provide the biologic basis for clinical trials to demonstrate more pronounced benefit for adjuvant systemic therapy.

Introduction

Lung cancer continues to be the leading cause of cancer deaths in the United States. Approximately 85% of lung cancer patients will have a non-small-cell histologic diagnosis for which surgical treatment offers the best chance of cure. Despite the high incidence of non-small-cell lung cancer (NSCLC), relatively few randomized trials have tested postoperative systemic therapy in these patients, and the accrual rates of studies that have been conducted have been small.

Given the high frequency of NSCLC, the paucity of randomized trials seems surprising at first. However, the small number of postoperative adjuvant trials can be explained in part by the fact that 75% of these patients have advanced disease and therefore are not surgical candidates.1 In addition, patients who are potential candidates (ie, stages I through IIIA) for postoperative adjuvant studies comprise a heterogeneous group2 so that clinical investigators are faced with the dilemma of combining groups of patients with significantly different survival outcomes. This results in an accrual rate that is higher than that obtained when using an approach of separating stages I through IIIA, which reduces the variation in survival but yields low accrual rates. Most trials have limited eligibility to patients with stage I disease only or to combined stages II and III disease. Another deterrent to achieving high accrual in adjuvant trials is the small number of thoracic surgeons involved in cooperative groups. Lastly, many potential protocol patients are excluded from adjuvant trials due to incomplete mediastinal lymph node dissections. All of these issues have impaired our ability to obtain sufficient data regarding the effectiveness of postoperative systemic therapy in NSCLC.

During the last 10 years, a large number of stage IIIA patients and some stage IIIB patients were entered in nonrandomized trials to test preoperative chemotherapy or chemoradiotherapy.3 The results of two small randomized trials evaluating preoperative chemotherapy have also been published.4,5 The number of clinical stage IIIA patients is virtually equivalent to the number of patients who have stage I, stage II,1 and clinically occult stage IIIA disease.6 Although the number of clinical stage IIIA patients is large, the concept of using preoperative chemotherapy or chemoradiotherapy is relatively new, and large randomized trials have not been completed. Therefore, the effect of preoperative chemotherapy on survival is unknown.

To review postoperative systemic treatment, we considered only randomized trials that were reported in manuscript form from 1986 to the present and included at least 50 patients. To review preoperative studies, we considered only large phase II trials and small randomized studies. We also address ongoing randomized studies and the design of potential new trials.

Postoperative Adjuvant Therapy

Since Matthews et al7 conducted their classic study in the 1970s, it has been well known that distant metastatic disease is the dominant site of recurrence in patients who have undergone a potentially curative resection for lung cancer. A more recent study8 in patients who had resected stage I NSCLC has shown that the first sites of recurrence involve distant sites. These observations served as the basis for trials of postoperative systemic therapy.

The rationale for these studies was based on not only a high rate of distant failure, but also the hypotheses that distant micrometastatic disease was present at the time of resection and that systemic therapy with either chemotherapy or immunotherapy might result in complete eradication of the micrometastatic disease. The earliest trials of chemotherapy, which consisted of single alkylating agents and nonspecific immunotherapy, have been addressed recently in a comprehensive review,9 and these trials are not discussed here. Our review is limited to adjuvant trials reported during or after 1986.

The individual modern trials of postoperative systemic therapy have included patients who had completely resected stage I through stage IIIA disease,10-17 as well as those who had incompletely resected disease (ie, tumors at the surgical margin or metastases in the highest mediastinal lymph node).18 In addition, some trials included only patients with lymph node metastasis (N1 and N2),14,15 while other trials included only patients without lymph node metastases (N0).11 Still others included lymph node-negative and -positive patients (N0, N1, N2).11-13,16,17 The studies in this review are divided into two categories: (1) late-stage; postoperative trials, in which either all or the majority of patients had metastases to hilar (N1) or to ipsilateral mediastinal (N2) lymph nodes, and (2) early-stage postoperative trials, in which either all or most patients were node negative.

Late-Stage Postoperative Adjuvant Trials

The treatment regimens and the survival results for randomized adjuvant studies in patients who had resected late-stage disease are summarized in Table 1. The Lung Cancer Study Group (LCSG) conducted three of these trials.14,15,18 Four to six courses of the same chemotherapy regimen cyclophosphamide/doxorubicin/ cisplatin (CAP) were used, but the standard treatment and the eligibility requirements differed among the three trials.

The earliest LCSG trial14 included patients who had adenocarcinoma or large-cell cancer that had metastasized to hilar (N1) or ipsilateral mediastinal (N2) lymph nodes. Patients with squamous-cell carcinoma were excluded. Following complete resection of intrathoracic disease, patients were randomly assigned to four courses of CAP chemotherapy or to immunotherapy consisting of intrapleural bacille Calmette-Guérin (BCG) and oral levamisole. Disease-free survival was significantly longer (log-rank P=.015) in CAP-treated patients. Also, the overall survival trend was better with CAP (median survival = seven months longer), but the results were not statistically significant (P=.078). Critics argued that the longer disease-free survival in the CAP group was due to a detrimental effect on survival from BCG and levamisole rather than to a positive effect from chemotherapy. This explanation seems unlikely because the survival results in BCG-treated patients were similar to resected stages II and III LCSG patients who were included in previous LCSG trials but did not receive systemic therapy. Although overall survival was not significantly different, these observations suggest that adjuvant CAP treatment produced a positive biologic effect in patients with stages II and III disease.

The second LCSG trial18 involved patients who had incompletely resected NSCLC (ie, metastatic disease in the highest ipsilateral mediastinal lymph node or microscopic disease at the surgical margins). Unlike the earlier LCSG study, patients with squamous-cell carcinoma were included in this trial. Following recovery from surgery, each patient received split-course thoracic radiation (4 Gy daily for five days, repeated 21 days later). The chemotherapy group received two courses of CAP simultaneously with split-course thoracic radiation followed by four additional courses of chemotherapy alone. The results of this trial were similar to those of the first LCSG study in that disease-free survival was significantly better for CAP-treated patients (P=.001), and the rates of recurrence and death were significantly lower in the chemotherapy group during the first year of follow-up. However, these differences disappeared during the second year, and again there was no long-term survival advantage from CAP chemotherapy.

In the third LCSG trial,15 patients who had completely resected stages II and III NSCLC (all histologies included) were randomized either to treatment with four courses of CAP chemotherapy beginning five weeks after surgery or to treatment with CAP when recurrent disease was detected. Again, no significant survival difference was observed, but there was a trend (P>.05) toward reduced risk of recurrence and death in the group treated with immediate chemotherapy.

European investigators also tested a postoperative regimen that included the CAP regimen.16 However, this CAP regimen was considerably different from that tested in the LCSG trials. Three courses of chemotherapy were administered. The first and third courses consisted of doxorubicin, vincristine, lomustine, and cisplatin, and the second course included cisplatin, vincristine, and cyclophosphamide. Patients with all types of NSCLC at stages I through IIIA were eligible for this trial. They were randomly assigned to immediate thoracic radiation or to three courses of chemotherapy followed by radiation. With an accrual of 267 patients, this was the largest of the late-stage postoperative adjuvant trials. The investigators again observed no significant differences in disease-free and overall survival, but there was a trend toward increased incidence of distant metastasis in the radiotherapy-only group (P=.09).

In another randomized trial,17 three courses of postoperative vindesine/cisplatin were compared with no additional treatment in 181 completely resected patients with stage III disease. The Japanese investigators chose the vindesine/cisplatin regimen because it was slightly superior to CAP in a Canadian trial19 that compared the two chemotherapy regimens to supportive care only in stage IV NSCLC patients. As postoperative therapy, the vindesine/cisplatin combination produced no significant differences in disease-free survival, overall survival, or patterns of failure.

In summary, the three consecutive LCSG studies14,15,18 that tested the CAP regimen in late-stage resected NSCLC patients showed a positive biologic effect (ie, delayed recurrence of disease). However, overall survival was not significantly different. In contrast, two other trials -- the European trial16 of the CAP regimen given on a different schedule than that used in the LCSG trials, and the Japanese trial17 testing vindesine/cisplatin as adjuvant therapy -- failed to show an impact on disease-free or overall survival.

Early-Stage Postoperative Adjuvant Trials

The results of these early-stage studies are summarized in Table 2. The first reported trial10 of treatment with postoperative platinum-containing chemotherapy in resected node-negative disease was conducted in Finland. This study included 110 subjects who were predominantly T1-2 N0 patients and a few T3 N0 patients. Compared with patients who received no postoperative treatment, those treated with CAP chemotherapy had significantly higher survival rates (10-year: 61% vs 48%; five-year: 67% vs 56%; P=0.05). If patients who died of apparent cardiac causes were excluded from the survival analysis, the P value was lower (P=0.019). Patients were scheduled to receive six courses of CAP, but this was accomplished in only 57% of cases. Thirteen percent of the 54 patients randomized to the chemotherapy arm failed to receive any chemotherapy. When survival was evaluated only in the 54 patients assigned to the chemotherapy arm, a five-year survival rate of 72% was observed in those who completed six cycles of CAP vs 50% in patients who did not receive six cycles (P=.15), thus suggesting that more chemotherapy might have a greater positive effect on survival.

The Lung Cancer Study Group conducted a similar trial in resected early-stage NSCLC patients.11 Unlike the Finnish study,10 all stage I patients (T1-2 N0 and T1 N1) were eligible. After recovering from surgery, patients were randomized to no additional treatment or to four courses of the CAP regimen. This regimen differed from the Finnish trial only in cisplatin dosage (60 mg/m2 in the LCSG trial vs 40 mg/m2 in the Finnish trial) and in schedule (four rather than six courses were given in the LCSG study).

More patients were entered on the LCSG study (267 vs 110 in the Finnish study) in which chemotherapy did not prolong either time to recurrence or survival, and the patterns of failure were identical. Compliance with the prescribed chemotherapy was poor: 20% of the patients assigned to the chemotherapy arm failed to receive any chemotherapy, and an additional 14% received only one course. Only 53% of the patients received all four courses of the planned chemotherapy. Unlike their late-stage adjuvant trials, the LCSG investigators did not observe a biologic effect from postoperative CAP in this group of patients. Although it is impossible to determine the reason for the apparent inconsistency for the results observed by LCSG investigators in early-stage11 vs late-stage14,15,18 patients, it is possible that the poor compliance observed in the early-stage trial may have been a factor.

In contrast to the conflicting results observed with the CAP regimen in early-stage patients, two groups of Japanese investigators12,13 reported significantly improved survival in patients who received one course of platinum-based chemotherapy plus prolonged oral administration of tegafur and uracil (UFT) combined at a molar rate of 1:4.

The first trial12 included 333 patients who had undergone resection of stages I through III NSCLC, with the majority of patients having stage I disease. The postoperative treatment consisted of one course of doxorubicin/cisplatin followed by six months of daily oral UFT vs no additional treatment. The five-year survival results for chemotherapy vs no treatment were 61.8% and 58.1%, respectively (P>.05). However, a significantly higher number of lymph node metastases were observed in the chemotherapy-treated group (35% vs 23%, P=.018). Using Cox's proportional hazard model to adjust for the imbalance in this nodal status and other pretreatment prognostic factors, the chemotherapy group had a significantly higher survival rate than the untreated group (P=.044).

In the more recent Japanese trial,13 323 patients were randomly assigned to no additional treatment or to three courses of vindesine/cisplatin plus daily UFT for one year or to daily UFT for one year. Although the majority of patients in this trial had stage I disease, stage II and III patients also were included. Statistical analyses revealed no significant imbalances among the three treatment groups with respect to stage or to other prognostic factors. The five-year survival rates for the UFT arm, the vindesine/cisplatin/UFT arm, and the control arm were 64.1% 60.6%, and 49.0%, respectively.

Based on these results, it appears that administration of daily oral UFT results in improvement in long-term survival in resected early-stage NSCLC patients. This is surprising since UFT produces response rates of only 6% and 8%20,21 in advanced NSCLC. However, with two trials showing improved survival with postoperative UFT,12,13 these observations should be considered when new trials are designed.

Meta-Analyses of Postoperative Adjuvant Therapy Trials

The preceding comments have been limited to modern randomized studies that included at least 50 patients and that have been published as manuscripts. However, a recent meta-analysis22 included all randomized trials testing postoperative chemotherapy or chemoradiotherapy that began accrual after January 1, 1965, and completed accrual by December 31, 1991. This effort showed that the absolute risk of death was reduced by 3% at two years and by 5% at five years for patients who were treated with postoperative cisplatin-containing regimens compared with patients who were treated with surgery alone (P=.08). Similarly, there was a 2% absolute reduction in the risk of death in patients treated with postoperative radiation and cisplatin-based chemotherapy compared with patients who received only postoperative radiation (P=.46). This change is not statistically significant. Long-term treatment with alkylating agents, which was done in the early randomized trials, actually appeared to increase the risk of death by 15% and translated into an absolute decrease in survival of 4% at two years and 5% at five years (P=.05). Although the results of the meta-analysis22 suggest that cisplatin chemotherapy regimens given postoperatively may result in a slight survival improvement, it should be noted that unlike the breast cancer meta-analyses that included 75,000 cases,23 the lung cancer meta-analysis was small. The meta-analysis that evaluated patients who had surgery with or without cisplatin chemotherapy included only 1,394 patients, and the group treated with surgery and radiation plus or minus cisplatin regimens included 668 patients. Based on the limited data, the heterogeneity of the patients, and the borderline P values, it is important that large, carefully conducted randomized trials be performed in this group of patients.

Recently Closed and Ongoing Randomized Trials of Postoperative Adjuvant Chemotherapy

An Intergroup adjuvant trial (EST 3590) that accrued 482 patients has been completed. Patients eligible for this study had completely resected NSCLC that had metastasized to hilar or ipsilateral mediastinal lymph nodes. Patients with enlarged mediastinal lymph nodes on preoperative chest computed tomography or preoperative histologic confirmation of mediastinal lymph node metastases were excluded from this study. Each patient received radiation therapy (50 Gy) to the mediastinum after recuperating from surgery, and patients were randomized to receive either four courses of etoposide/cisplatin or no additional therapy. Two of the courses of chemotherapy were given during radiation, and two were given after completion of radiation. This trial is important because of the large number of patients entered, because all non-small-cell histologies were included, and because a complete lymph node dissection was done on each patient. The size of this trial approaches the total number of patients who received similar postoperative treatment (radiation vs chemoradiation) and who were included in the recent meta-analysis.22

Several trials are underway to test postoperative chemotherapy in patients with completely resected NSCLC (Table 3), and two ongoing European trials are evaluating postoperative chemotherapy in patients with stages I through IIIA disease. Each of these protocols is testing older chemotherapy regimens. In the EU-94043 trial, mitomycin/vindesine/cisplatin is being compared to no systemic therapy, and in the EU-96010 study, the chemotherapy regimen has not been specified. Investigators have the option of using cisplatin combined with either etoposide or a vinca alkaloid. In each trial, postoperative radiation can be given at the discretion of the physician.

Two North American studies are testing chemotherapy regimens that include newer agents. Canadian physicians are participating in a trial (NCIC-BR-10) in which patients who have undergone resection of T2 N0 or T1-2 N1 NSCLC are randomized to vinorelbine/cisplatin or to no additional treatment. This study recently has become an Intergroup trial. Investigators in the Cancer and Leukemia Group B study (CLB-9633) are comparing carboplatin/paclitaxel to observation only following resection of T2 N0 NSCLC.

Preoperative Therapy

The use of preoperative systemic therapy with or without concurrent thoracic radiation is termed neoadjuvant therapy or induction therapy. Assuming that virtually all of the stage IIIA NSCLC patients are candidates for preoperative systemic therapy, the total number of patients with this stage (22% of all NSCLC patients) is virtually the same as the total number of patients who present with early-stage lung cancer (clinical stages I and II, 23%).1 Many nonrandomized trials have been conducted in this group of patients.3 Some investigators have used preoperative chemotherapy alone,24,25 while others have used chemotherapy and concurrent radiation therapy.26,27

There are several reasons for using systemic therapy prior to pulmonary resection. First, most of these patients will have distant micrometastatic disease. Using preoperative chemotherapy provides the earliest opportunity to treat the widespread subclinical disease. In addition, the response rate to chemotherapy in patients with locally advanced disease is approximately twice as high as that in patients with stage IV disease.28 The use of chemotherapy at this point might enable resection of some lesions that were initially considered to be unresectable marginally; and it provides the opportunity to sterilize mediastinal lymph node metastases.

Several large phase II studies of preoperative chemotherapy or chemoradiotherapy have been performed.24,25 Comparing results from these trials is difficult. First, the staging procedures were inconsistent. Mediastinoscopy was required in some trials, while in others, the computed tomography chest scan alone was used for mediastinal lymph node staging. Second, the eligibility requirements were inconsistent. Some investigators included only patients with biopsy-proven ipsilateral mediastinal lymph node metastases (N2 disease), while others included patients whose disease was classified as stage T3 N0, which is a more favorable group of stage IIIA patients. Still others included patients with metastases to the contralateral mediastinal lymph nodes (N3/stage IIIB). The results of most of these studies suggested that surgery was feasible following preoperative treatment with chemotherapy or chemoradiotherapy. The one possible exception was the mitomycin/vinblastine/cisplatin (MVP) regimen, which was associated with high treatment-related mortality in one study25 and low lethal toxicity in another trial.24

The results from many of these combined modality trials3,24-27 appeared to be better than those observed for radiation alone29 or surgery alone2 in patients with stage III NSCLC. However, whether this is due to a positive effective from preoperative treatment or to selection of patients with better initial prognosis is difficult to determine. The apparent improved survival may be
due partly to stage migration because the computed tomography scans of the chest, abdomen, and brain have been done routinely in the recent phase II trials. This factor probably eliminated a significant number of patients with clinically occult stage IV disease who would have been included in earlier trials that tested either radiation29 or surgery alone.2

Although the multiple trials testing preoperative treatment of patients with stage III lung cancer have not provided a definitive answer regarding its effectiveness, it appears that the use of preoperative treatment using cisplatin-containing chemotherapy with or without radiation therapy is feasible,3 with the possible exception of excessive toxicity from regimens containing mitomycin.24 In addition, the encouraging survival results have served as the basis for two small randomized trials4,5 and several large ongoing phase III trials. The phase II trials also have provided several interesting observations. First, preoperative treatment results in complete clearance of tumor in the resected specimen in approximately 15% of patients.24,26,27 Despite the inconsistency of the results,27 it appears that a histologically confirmed complete remission has prognostic significance, with significantly longer survival being observed in patients whose resected specimens contain no residual tumor.30,31 Similarly, significantly better survival results are seen in patients with metastases to ipsilateral mediastinal lymph nodes prior to treatment but in whom no tumor is found in the lymph nodes following treatment with chemoradiotherapy.27,32 Both of these parameters should be considered as major endpoints in trials to test new preoperative regimens.

Two small randomized trials4,5 have been conducted comparing surgery alone vs three courses of cisplatin-containing chemotherapy followed by surgery (Table 4). The first trial was conducted in Spain4 and used mitomycin, ifosfamide, and cisplatin as the induction regimen. The second trial was conducted at M.D. Anderson Cancer Center5 and used a regimen consisting of cyclophosphamide, etoposide, and cisplatin. Although the trials are small, both showed significantly improved survival for patients who received preoperative chemotherapy and surgery compared with those who were treated with surgery alone. The inclusion of mitomycin in the chemotherapy regimen did not result in significant preoperative or postoperative complications.

The difference in survival in these trials is striking. The survival results of the chemotherapy and surgery in both of these trials were not as good as those seen in some of the larger phase II trials.24-27 These differences may be due to the fact that patients in the small randomized trials were selected more carefully. In the trial by Rosell et al,4 the large difference in survival between patients who received surgery alone compared with those who received chemotherapy followed by surgery may be explained in part by the fact that there was a higher percentage of the ras oncogene in the tumors of the surgery-only patients. Previous studies have shown that patients whose tumors contain the ras mutation have a particularly poor prognosis.33

Ongoing Trials of Preoperative Treatment


Several phase III trials to evaluate preoperative treatment are underway (Table 5) and are addressing four questions. (1) Does preoperative chemotherapy have any benefit compared to surgery alone? (2) Is there a significant difference between sequential chemotherapy and radiation vs sequential chemotherapy and surgery? (3) Does surgery add anything to combined modality therapy consisting of chemotherapy and radiation? (4) Does combined chemotherapy and surgery have an advantage over radiation therapy alone?

The first question is being addressed by French investigators who are comparing surgery alone to mitomycin/ifosfamide/cisplatin (MIC) chemotherapy followed by surgery.34 Unlike the early randomized study that included only patients with stage III disease, this trial includes patients with stage I through stage IIIA disease. Approximately 200 patients were entered in this trial when preliminary results were presented in 1993.

Results of recent trials have shown that treatment with sequential chemotherapy and radiation produces superior survival compared to radiation alone. In particular, regimens in which cisplatin was combined with a vinca alkaloid have shown superior survival compared to radiation therapy alone.35-37 A recent meta-analysis22 evaluating multiple types of chemotherapy has demonstrated a small but significant improvement in the two-year and five-year survival rates for chemoradiotherapy. Based on these observations, European investigators are comparing platinum-containing chemotherapy followed by either radiation or surgery. A specific chemotherapy regimen is not mandated in this study.

To address the third question, an Intergroup trial (RTOG-9309) is being conducted in North America in patients with stage IIIA (N2) disease. Every patient is initially treated with cisplatin, etoposide, and simultaneous thoracic radiation. After receiving two courses of chemotherapy and 45 Gy of thoracic radiation, patients are randomized to either surgery or additional radiation. The large phase II trial conducted by the Southwest Oncology Group (SWOG) is the basis for this study.27

The fourth question is being evaluated by multiple European investigators who are conducting a randomized trial (EU-95041) comparing mitomycin-containing chemotherapy followed by surgery when feasible or by radiation vs radiation alone. A British trial (MRCLU-20) is also comparing survival in patients who are treated with chemotherapy consisting either of mitomycin/vinblastine/cisplatin or of mitomycin/ ifosfamide/cisplatin followed by surgery when feasible or by radiation when surgery is not feasible. The treatment group (chemotherapy followed by local therapy) is being compared with patients treated with radiation alone.

Future Directions

Progress in the systemic treatment of NSCLC has been hindered by the relative lack of effective single agents. Five new single agents that produce response rates of 20% or higher in NSCLC have recently been identified.38 One of these agents, vinorelbine, has been tested extensively in large phase III trials.39-41 A combination of vinorelbine/cisplatin has been compared to vinorelbine alone in two French trials39,40 and to cisplatin alone in a SWOG trial.41 Superior survival and higher response rates were observed for the two-drug combination.39,41 In the randomized trial by Depierre et al,40 vinorelbine/cisplatin produced higher response rates and longer disease-free survival compared with vinorelbine alone; however, overall survival was not significantly different from vinorelbine alone. Perhaps more importantly, in the first French trial,40 vinorelbine/cisplatin was compared with vindesine/cisplatin, and significantly longer survival was observed in patients treated with vinorelbine/cisplatin.

Paclitaxel has also been combined with cisplatin and evaluated in a large phase III trial conducted by the Eastern Cooperative Oncology Group.42 The preliminary results showed a significantly higher response rate for paclitaxel/cisplatin compared with etoposide/cisplatin.

Based on the superior results with vinorelbine/cisplatin and the higher response rates with paclitaxel/ cisplatin in patients with more advanced NSCLC, these agents should be tested in patients with less advanced disease who may benefit from the effect of such agents on long-term survival. As noted earlier, vinorelbine/cisplatin is currently being evaluated as postoperative treatment in patients who have undergone resection of T2 N0 or T1-2 N1 NSCLC. The paclitaxel/carboplatin regimen is also being tested following resection of T2 N0 NSCLC in a CALGB trial. Although results of the
relatively large multi-institutional study comparing paclitaxel/carboplatin to etoposide/cisplatin are not currently available, this regimen has been selected for analysis in an adjuvant setting because it has been associated with high response rates and long survival in phase II studies.43,44

Patients with resected N2 disease are being studied in two ongoing European trials in which the new chemotherapeutic agents are not specifically being tested. In one trial, the patients are treated with platinum combined with a vinca alkaloid, but the vinca alkaloid is not specified. Although some investigators may choose to use a vinorelbine/platinum combination, the study is not specifically designed to test the impact of the vinorelbine/cisplatin regimen on survival. These trials include patients with stages I through IIIA (N2) disease, and there may not be a sufficient number of resected N2 patients to determine the effectiveness of chemotherapy in the node-positive patients.

No active protocol is currently testing postoperative chemotherapy in resected N2 patients in North America. What should be done with this group of patients while results from the recently completed Intergroup trial (EST 3590) are maturing? An argument could be made to initiate a trial testing newer agents. The late-stage LCSG trials and the meta-analysis that included both early- and late-stage resected patients showed a trend for longer survival in patients treated with postoperative cisplatin-containing chemotherapy. Assuming that the results of the recently completed Intergroup trial will show at least a trend for longer survival in the patients treated with etoposide/cisplatin and concurrent radiation therapy, it would be reasonable to initiate a trial evaluating the new agents. The design could compare one of the newer chemotherapy regimens -- vinorelbine/cisplatin or paclitaxel plus a platinum compound -- with a "no-treatment" arm. On the other hand, perhaps a study design representing a "leap of faith" could be considered. In this type of trial, the "no-treatment" arm would be eliminated and vinorelbine/cisplatin could be compared with paclitaxel/carboplatin, a comparison that is currently being studied by the SWOG in more advanced disease. It would be difficult to argue with critics who would maintain that a no-treatment arm is essential for this type of study. However, a trial that included two chemotherapy arms probably would have more rapid accrual, and it would provide significant information regarding survival for N2 patients treated with new chemotherapy regimens.

The design of future trials in patients with more advanced disease (histologically confirmed, ipsilateral mediastinal lymph node metastases identified prior to surgery or T4 lesions) is more complex. What is the role of surgery in these patients? How should the new agents be included in patients with more advanced stage III disease? Although the results of the small randomized trials have shown longer survival in patients treated with chemotherapy followed by surgery,4,5 most clinicians have not adopted sequential chemotherapy and surgery as standard treatment for patients with ipsilateral mediastinal lymph node (N2) metastases. It is likely that the French trial,34 in which surgery alone is compared with the MIC regimen followed by surgery, will have important implications for the design of future trials testing preoperative chemotherapy. If the number of stage IIIA patients is inadequate to determine the survival effect of treatment with the MIC regimen, this approach may become the standard regimen against which new preoperative regimens (eg, vinorelbine/cisplatin or paclitaxel/platinum) could be compared. On the other hand, if preoperative treatment with the MIC regimen shows no advantage over surgery alone, then the randomized studies that are evaluating the role of surgery in patients with locally advanced disease will become increasingly important.

With the availability of new chemotherapeutic agents, as well as the emergence of new biologic therapies including gene therapy, clinical investigators need to develop more extensive collaboration on both national and international levels. They must agree on the most important questions, select the regimens to test these questions, and decide which groups will conduct the different trials.

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From the Rush University Medical Center, Chicago, Ill.

Address reprint requests to Dr Bonomi at the Section of Medical Oncology, Rush University Medical Center, 1725 West Harrison St, Suite 821, Chicago, IL 60612.

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