Perhaps no greater controversy exists in the management of non-small-cell lung cancer than the multimodality treatment of stage III disease, which includesor potentially could includesurgery. This controversy exists in part because many published pilot studies, and several small randomized trials as well, addressed a wide range of stage III subsets with inconsistent pathologic documentation of nodal status. Thus, as Table 1 illustrates, the critical question differs for two major groups. In the group with minimal, nonbulky disease, initial surgical resection has been the standard of care. These subsets include T3N0 or N1, nonenlarged N2 nodes on computed tomography(CT) scan, and negative CT scan with microscopic N2 disease only. The debate here is whether preoperative chemotherapy with or without radiotherapy definitely improves survival over surgery alone. For the group with nonminimal, bulky disease, chemoradiotherapy is the current standard of care. These tumors include bulky N2 disease on CT scan or chest x-ray, T4 (no effusion) primaries, and N3 disease. The controversy in this group is whether surgical resection after induction chemoradiotherapy improves outcome over chemoradiotherapy alone.
Therefore, the objectives of this review are to update and provide perspective on these two critical questions and to consider whether the data are sufficient to recommend new standards of care for these two groups. This article will also address several other aspects of this controversy: Is there an optimal induction regimen? Should radiation be sequenced or given concurrently with chemotherapy? Is there a defined role yet for the new agents (with or without radiation) given before surgery?
The interpretation of bimodality and trimodality trials that include surgery for stage III non-small-cell lung cancer requires attention to the definition of stage subsets and the method of their documentation (radiograph only vs histologic proof of N2, N3, or T4 status). Trial protocols vary regarding which patients undergo surgery (those with stable disease or just those with responding tumors), and in their definitions of complete resection as well (most use resection of gross disease, but a few require negative margins). Other factors in these reports that may have a variable influence on survival include the definition of "bulky" disease, the presence of single intranodal N2 disease, the involvement of nodal stations N5 or N6 only, and positive N7 nodes. Above all, it is critical that resection rates and overall survival be presented for the entire denominator, not just for those who undergo thoracotomy. Predictors of long-term survival should optimally be addressed in multivariate models.
Several comprehensive reviews outline the historical development of neoadjuvant, or induction (currently the preferred term), approaches in stage III non-small-cell lung cancer.[1-4] Initially, the paradigm was to use induction radiotherapy or chemotherapy, or both, to render unresectable disease resectable. The early enthusiasm for preoperative radiation alone waned[5,6] but was resurrected (to add to chemotherapy) when the results of randomized studies favoring chemoradiotherapy over radiation alone emerged (see review by H. Wagner, Jr.). Therefore, the paradigm for bimodality and trimodality trials recently shifted such that the goal of these approaches is to provide initial control of both bulky disease and distant micrometastases with induction therapy and then to employ surgical resection for optimal local control.
The early feasibility studies were performed in the era of the initial paradigm.[7-10] In large part, these trials used first-generation chemotherapy regimens with low-dose cisplatin (Platinol) and radiation added variably. Staging usually was clinical, and patient subsets often included those with N0 or N1 stage III disease. Nevertheless, these were pivotal studies in that they demonstrated the general safety of surgery after induction therapy and provided intriguing survival data.
Therefore, an impetus existed for larger trials, many of which had more selected stage subsets and documented disease pathologically. Those trials that addressed nonminimal, bulky, or mixed-bulk disease will be considered first, followed by the randomized studies of patients with minimal-bulk, resectable tumors.
Several trials were conducted that used preoperative vinblastine (Velban) and cisplatin with or without mitomycin (Mutamycin) (MVP or VP) in patients with pathologically documented N2 disease.[6,11-14] Table 2 summarizes these studies. Radiation was given variably in these trials (intraoperatively, postoperatively, or not at all), which makes comparison of outcomes among the studies difficult. Resection rates of the entire denominator were 50% to 65%, with operative mortalities of 3.1% to 17%. In addition, significant pulmonary morbidity, primarily in the postoperative period, was observed in these studies (eg, 13% in the Memorial Sloan-Kettering Cancer Center [New York] study only 42% of patients completed the planned treatment (all radiation was given postoperatively).
Median survivals in these four studies were 13, 15, 19, and 21 months. Of note, in a recent update, the Toronto investigators reported a survival plateau between 3 and 5 years, with a persistent 34% survival (Ronald Burkes, MD, personal communication, February 1996). Two of these reports included sites of first failure: locoregional- only relapse occurred in 26% and 25% of patients.
The next series of studies included those that used concurrent chemoradiotherapy (radiation began on day 1 of chemotherapy), as outlined in Table 3.[15-18] Eligibility for these trials was more variable, in that a wider range of stage IIIA subsets were included: some patients had T3N0 or N1 disease in the Rush-Presbyterian (Chicago) and CALGB studies, whereas the Southwest Oncology Group (SWOG) and Lung Cancer Study Group trials enrolled only the N2 subset of patients with stage IIIA disease. In addition, T4 and/or N3 subset patients with IIIB disease were included to varying degrees in all but the CALGB study. Furthermore, all but the Rush-Presbyterian study required pathologic-documentation of N2, T4, or N3 status. The SWOG trial was designed only for patients with bulky disease, whereas the others allowed a mix of minimal-bulk and bulky presentations. Thus, comparison of outcome among these studies is difficult.
As Table 3 shows, complete resection rates of the entire denominator were 52% to 71%, with operative mortalities of 4% to 15% (again, these were predominantly pulmonary-related deaths). The median survivals in the two studies that excluded T3N0_1 tumors were 15 and 13 months,[15,16] whereas the other two trials, with approximately 20% of patients in this category, had median survivals of 22 and 16 months.[17,18] Patterns of first recurrence were reported in detail by the SWOG: 11% were locoregional only, whereas 61% were distant alone. A significant proportion of the latter occurred in the brain only.
The majority of patients enrolled in trials of induction chemotherapy or chemoradiotherapy followed by surgery had stage IIIA disease. Less is known regarding outcome in those with selected IIIB subsets. The second Lung Cancer Study Group trial and the Rush-Presbyterian study (Table 3) included patients with clinically staged "minimal T4" and "selected T4" lesions, respectively. Separate survival data for this subset are not provided. Two groups reported equivalence in outcome in combined-modality trials for clinical stage IIIA and IIIB disease.[19,20] The T4N0 subset was suggested to have a better outcome, as was the T3N0 subset in the IIIA group.
The SWOG trial alone included patients who had pathologically documented T4 or N3 disease. The outcome for this subset was analyzed separately. The median, 2-year, and 3-year survivals were identical for the IIIA(N2) vs the IIIB group. Notably, patients with the T4 subset had outcomes identical to those with T1N2 disease and achieved a 2-year survival of 64%. A follow-up trial for patients with pathologic stage IIIB disease by the SWOG used identical chemoradiotherapy, but no surgery was performed. Instead, the radiation dose was increased from 45 to 61 Gy. The 2-year survival for the T4 N0 or N1 subset was only 33%. This historical comparison of consecutive trials suggests that surgery might be beneficial in this select T4 group without N2 or N3 involvement, but a prospective randomized study is required to validate this observation.
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