Induction Chemotherapy With/Without Radiation Followed by Surgery in Stage III Non-Small-Cell Lung Cancer

Kathy S. Albain, MD

Oncology, ONCOLOGY Vol 11 No 9, Volume 11, Issue 9

The objectives of this review are to provide an update and perspectives on the use of induction therapy (chemotherapy with or without radiotherapy) followed by surgery in two subgroups of patients with stage III non-

ABSTRACT: The objectives of this review are to provide an update and perspectives on the use of induction therapy (chemotherapy with or without radiotherapy) followed by surgery in two subgroups of patients with stage III non-small-cell lung cancer. The first subset is that of bulky stage IIIAN2 or IIIB disease (standard treatment: chemoradiotherapy), and the second, minimal stage IIIA non-N2 or computed tomography (CT)-negative N2 disease (standard therapy: initial surgical resection). Details of recent major trials in each of these two subsets are provided regarding selections criteria, study design, toxicity, resection rates, median and long-term survival, and predictors of survival. The review concludes with a discussion of whether consensus has emerged about the addition of surgery after induction chemoradiotherapy in the group with bulky disease and whether there should now be a standard recommendation for preoperative chemotherapy with or without radiotherapy in patients with resectable tumors. [ONCOLOGY 11(Suppl 9):51-57, 1997]

Introduction

Perhaps no greater controversy exists in the management of non-small-cell lung cancer than the multimodality treatment of stage III disease, which includes—or potentially could include—surgery. 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?

Caveats

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.

The Early Studies

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.

Nonminimal, Bulky, or Mixed-Bulk Disease

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).[14]

Median survivals in these four studies were 13, 15, 19, and 21 months. Of note, in a recent update, the Toronto investigators[13] 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%[11] and 25%[14] 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.[15] 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.[15] 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.[21] 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.

Minimal, Nonbulky, Resectable Disease

Four small randomized trials in patients with resectablenon-small-cell lung cancer were conducted in which surgery alone was compared with induction chemotherapy with or without variably timed radiation.[22-25] Table 4 provides the details of these programs. Although some of the trials reviewed in the preceding section included a subset of patients with initially resectable disease, the majority did not. This is in contrast to the studies in Table 4, where surgery alone was deemed the standard for these patients with, for the most part, minimal, nonbulky disease. The first two trials are not usually discussed, whereas the latter two have provoked much debate. All four will now be considered.

The National Cancer Institute trial was perhaps ahead of its time, since it had to be closed before its accrual goal had been met due to lack of referrals.[22] The patients had minimal-bulk disease, but microscopic N2 involvement was first documented by mediastinoscopy or biopsy. No statistically significant difference emerged between the two arms initially, although with long-term follow-up, the P value has continued to decrease in favor of the chemotherapy arm (Harvey Pass, MD, personal communication, January 1996). Another randomized study, considered only rarely, was performed in Japan in patients with clinical stage IIIA and select IIIB disease.[23] The group that received preoperative chemoradiotherapy had a survival identical to those in the surgery-only arm.

As noted, the other two randomized trials in minimal bulk disease generated much discussion and debate based on their strongly positive results favoring the induction chemotherapy arms.[24,25] Both were conducted with 60 patients who had predominantly stage IIIA disease; N2 involvement was not required and mediastinoscopy was not mandated if computed tomography of the mediastinum was negative. The M. D. Anderson Cancer Center study found 40% of patients in the surgery-only arm had stage IIIB or IV disease, which alternately might explain the observed survival difference. In contrast, patients in the surgery arm of the Spanish trial[25] had surprisingly poor survival, even though 37% of them had N0 or N1 disease. Both studies closed early due to the marked survival differences. However, it is not clear whether the early stopping rules for these very small trials accounted for the strong potential influence of even slight imbalances in substage or molecular prognostic factors between the two arms. Ongoing randomized trials are attempting to validate these encouraging findings.

Long-Term Survival

Several of the trials reviewed in the previous two sections provided long-term survival data and assessed its predictors (Table 5). These studies differed vastly in several critical aspects: (1) disease bulk, (2) which stage III subsets were included, and (3) whether pathologic documentation of N2 disease was required. Eligible subsets varied widely. Included were patients with very minimal-bulk disease and no requirement for documentation of N2 disease (the two very small randomized studies of preoperative chemotherapy vs surgery alone);[24,25] a mix of stage III subsets with no pathologic documentation;[17] bulky, pathologically documented N2 presentations;[14,15] and mixed bulk but pathologically documented N2 disease.[12,13] These stage subset variations and possible inaccurate staging on clinical grounds may explain the wide range of 3- to 5-year survivals shown.

No trial, except, perhaps, the recent update of the Toronto experience (Ronald Burkes, MD, personal communication, February 1996), has demonstrated a clear plateau on the tail of the survival curves. This may be due in large part to competing causes of death. Only the SWOG trial attempted to categorize the reasons for death, rather than assuming they were cancer related.[15] Cancer did account for 64% of all deaths, but 20% were caused by late pneumonia (long after the end of treatment), myocardial infarction, pulmonary embolus, cerebrovascular accidents, trauma, ulcer, or second primaries.

Five studies reported analyses of the predictors of long-term survival after induction chemotherapy with or without radiation followed by surgery (Table 5). Methods of analysis varied (univariate, multivariate). The predictors observed included pathologic complete response (occurs in approximately 20% of specimens collectively across trials), complete resection, non-N2 IIIA disease, and pathologic clearance of mediastinal disease. The latter observation is of interest, given that it emerged as the only significant factor in a multivariate model that included complete resection rate, pathologic complete response, and multiple other factors.[15] The other reports did not assess this variable.

The implication of this finding is that clearance of disease in the mediastinum may be a surrogate marker for eradication of distant chemotherapy-sensitive micrometastases such that these patients may be the best candidates for additional postoperative chemotherapy. Thus, persistent N2 or N3 disease after induction may predict the presence of distant resistant disease. This raises the question of whether surgical resection is necessary if induction therapy has cleared mediastinal disease or whether these patients are the best candidates for optimal local control. Whether molecular correlates obtained from biopsy material before or after induction therapy could improve identification of the optimal patients for surgical resection awaits the results of ongoing studies.

Other Important Considerations

Other important factors to consider in this debate include treatment-related morbidity, whether an "optimal" induction chemotherapy has emerged, whether radiation is needed in the presurgery induction treatment and, if so, should it be sequenced or given concurrently with chemotherapy. Pilot studies that include hyperfractionated radiation and new agents should also be considered.

The morbidity resulting from induction chemoradiotherapy followed by surgery is not insignificant. Apart from the expected myelosuppression from chemotherapy and esophagitis from chemoradiotherapy, both usually quite manageable on an outpatient basis, postoperative pulmonary toxicity is the greatest concern. This is often either an extensive pneumonitis or an acute respiratory distress syndrome-like picture, the latter of which has a high mortality rate. Pulmonary morbidity and mortality were reported in most studies of combined-modality therapy at rates higher than those expected with radiation or surgery alone.[26-29] It occurred with all types of induction chemotherapy regimens, with or without radiation, and from multifactorial causes. The preoperative diffusion capacity of the lung for carbon monoxide may be the most important screen for this problem. It is being studied prospectively in the current Intergroup trial of patients with N2 disease.

One other morbidity often neglected in discussions is the posttreatment constitutional syndrome some patients experience (thoracotomy pain, malaise, anorexia, poor pulmonary reserve). This syndrome probably occurs at a greater frequency with induction therapy than with radiation or surgery alone. It often resolves within a year after treatment, but its lingering presence is clearly discouraging to the patient and the caregiver. Prospective quality-of-life analyses in this population are needed.

Finally, it must be emphasized that these programs were tested in the "fittest" patients, ie, those who were fully ambulatory and had general medical conditions that permitted the rigors of combined-modality therapy. Clinical trials geared to the large group of patients ineligible for these approaches are expanding, with first reports expected shortly.

Clearly, no induction program has emerged as optimal to date. In particular, no chemotherapy regimen can currently be recommended as superior, and no randomized trials have asked this question. All trials with published safety data have used second-generation cisplatin combinations, either in sequence or concurrently with radiation. Recent data suggest that patients with unresectable stage III disease (no surgery), achieved better survival with concurrent cisplatin/etoposide and radiation than with cisplatin and radiation (Avignon randomized trial, personal communication, June 1996). The addition of etoposide was an independent favorable predictor of survival in a multivariate model. The Brazilian study of chemoradiotherapy vs chemotherapy followed by surgery stands alone regarding the need for induction radiation.[29] In these patients with mixed stage III disease, survival was significantly better for those who received induction chemoradiotherapy than for those who received chemotherapy before and after surgery.

The optimal timing of radiation with respect to induction chemotherapy is also controversial. Some contend that concurrent induction chemoradiotherapy is more toxic than sequential administration, and that, in patients with unresectable disease, no data support the use of concurrent chemoradiotherapy over radiation alone. Careful review, however, of the toxicity profiles from the trials discussed here suggest they are quite similar, regardless of how radiation is given. In fact, the CALGB had great difficulty completing radiotherapy when it followed surgery.[14] Furthermore, in a nonsurgical trial the North Central Cancer Treatment Group reported that concurrent chemoradiotherapy increased the time to disease progression significantly and lowered systemic failure rates compared with radiation alone.[30] While no trials have been conducted with postinduction surgery to address the concurrent chemoradiotherapy vs sequential approach, an important Japanese study recently reported follow-up data from patients with unresectable stage III disease. The study concluded that there is a significant long-term survival advantage to the concurrent over the sequenced regimen.[31] Results of the ongoing Radiation Therapy Oncology Group trial addressing this question are awaited, although no surgery is given in this study.

Finally, has a role for preoperative hyperfractionated radiotherapy with chemotherapy been defined, and should the presurgery induction approach of the trials just reviewed be replaced by chemoradiotherapy incorporating new agents (eg, the taxanes, vinorelbine, or gemcitabine plus cisplatin or carboplatin)? Several studies that test the addition of hyperfractionated radiation to induction chemotherapy are in progress with results expected soon. Also in progress are phase II trials to establish the safety of the new agents in induction chemotherapy, first without and, eventually, with surgery. Some results have been published in abstract form, but so far no pilot data demonstrate the superiority of these regimens over the induction regimens reviewed here. As these studies mature, monitoring the stage subset mix and substage documentation methods will be critical to determine whether reports of superiority can truly be attributed to the change in chemotherapy. Thus, with no existing data to argue the safety and superiority of newer chemoradiotherapy induction regimens before surgery, the continued inclusion of second-generation chemotherapy with radiation in the current ongoing randomized trials can be justified.

Has a Consensus Emerged?

Should postinduction surgery become the standard of care in patients with stage IIIA disease and, if so, for which patient subsets? Many practitioners have concluded yes and prescribe this approach for all subgroups. As an upcoming majority consensus statement of the International Association for the Study of Lung Cancer will emphasize, the data argue that this conclusion is premature. The two groups identified at the beginning of this review must be considered separately. First, surgery following chemoradiotherapy has not been proven to be superior to chemoradiotherapy alone and should not be applied routinely to patients with unresectable bulky N2 or IIIB disease. Second, the value of preoperative chemoradiotherapy or chemotherapy alone over surgery alone in minimal-bulk, initially resectable subsets remains unsettled, based on the small numbers and stage subset biases in the two randomized trials that addressed this issue.

Ongoing worldwide randomized combined-modality trials that include surgery and have careful subset selection are addressing these two major questions in patients with both bulky and minimal-bulk disease. The current High Priority North American Intergroup Trial 0139 (Radiation Therapy Oncology Group, SWOG, Eastern Cooperative Oncology Group, CALGB, North Central Cancer Treatment Group, and National Cancer Institute of Canada) is testing the trimodality program developed by the SWOG[15] vs the same induction treatment but no surgery with full-dose radiation and concurrent chemotherapy in patients with pathologically documented bulky N2 disease. A European study asks whether preoperative chemotherapy adds to surgery alone in patients with resectable, minimal-bulk disease. Another trial plans to test the role of surgery in selected patients with stage IIIB disease.

It is hoped that oncologists and thoracic surgeons will allow these critical questions to be answered. The growing trends to attempt resection of disease in all patients following chemotherapy with or without radiotherapy, and/or to add new agents to induction radiotherapy ahead of published pilot safety and efficacy data in clearly defined subsets could jeopardize the worldwide accrual to these trials. If so, this will remain the most controversial area in the management of non-small-cell lung cancer for years to come.

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