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Ann Thorac Surg 1996;61:1564-1572
© 1996 The Society of Thoracic Surgeons

Current Reviews

Multimodality Therapy in Stage III Non-Small Cell Lung Cancer

Martin J. Edelman, MD, David R. Gandara, Mack Roach, III, MD, John R. Benfield, MD

Divisions of Hematology/Oncology and Cardiothoracic Surgery, University of California, Davis, and VA Northern California Health Care System, Martinez; and Department of Radiation Oncology, University of California, San Francisco, California


   Abstract
Top
 Footnotes
 Abstract
Introduction
 Therapeutic Modalities
 Study End Points
 Approach to Combined Modality...
 Future Directions
 Conclusions
 References
 
Background. Non-small cell lung cancer commonly presents as locally advanced disease. This category of tumors is heterogeneous. Although some patients clearly benefit from operative management alone, the vast majority (more than 90%) will succumb to their disease within 5 years. In the past decade a large clinical research effort has been undertaken in an attempt to improve on this outcome using a combination of chemotherapy, radiotherapy, and operation.

Methods. The English-language literature was reviewed using the headings for lung neoplasms and text words combined modality therapy and multimodality therapy. In addition, the bibliographies of relevant articles were reviewed. Emphasis was placed on prospective randomized trials and large phase II studies. We review the rationale, design, and outcome of these trials, including both operative and nonoperative approaches.

Results. Several prospective, randomized trials now demonstrate an advantage to combined modality management over radiotherapy or operation alone when a cisplatin-based chemotherapy regimen is incorporated into the treatment plan. This advantage was seen using both operative and nonoperative approaches.

Conclusions. Combined modality therapy offers an improved outcome for patients with stage III non-small cell lung cancer. Whether both operation and radiotherapy are needed for local control, the best sequence of treatment and the optimal chemotherapy regimen remain to be defined.


   Introduction
Top
 Footnotes
 Abstract
 Introduction
Therapeutic Modalities
 Study End Points
 Approach to Combined Modality...
 Future Directions
 Conclusions
 References
 
Locally advanced non-small cell lung cancer (NSCLC) is a common problem, with almost 50,000 new cases per year in the United States [1]. This category of NSCLC comprises a heterogeneous group of tumors that require meticulous staging because of potentially different approaches to management. In 1986, Mountain [2] published a new staging system for lung cancer. Application of this staging system in NSCLC has become standard to compare meaningfully data from various clinical trials in search of optimal approaches to therapy.

The term ``locally advanced'' as applied in this review refers to stage IIIA and IIIB NSCLC as defined by this staging system. Table 1Go illustrates staging criteria for IIIA and IIIB and the marked variability within the two substages, with five distinct subgroups of stage III disease. Stage IIIA designates a centrally located primary tumor near the carina (T3) limited extrapulmonary extension of the primary tumor (T3), and/or ipsilateral mediastinal lymph node metastasis (N2). Stage IIIB consists of direct extension of the primary tumor into the mediastinum, adjacent organs, or structures (T4), malignant pleural effusion (T4), or metastases to the contralateral mediastinum or supraclavicular and scalene nodes (N3).


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  		Table 1. . Clinically Distinct Subgroups Within Stage III NSCLC
 
Although it would be reasonable to assume that this heterogeneity in stage would lead to variability in natural history and prognosis, this factor has only recently been considered in the design of clinical trials in NSCLC. Within TNM subsets, there is often marked variability in prognosis. For example, nodal status within a T subset has major prognostic importance. Patients with T3 N0 tumors, commonly located peripherally or in the superior sulcus, have a better prognosis than other stage IIIA cancers, with a 30% to 50% 5-year survival after surgical resection in some reports [3]. In contrast, T3 tumors with ipsilateral mediastinal nodal involvement (N2) treated surgically show a sharp drop-off in survival. The surgical series of Pearson and co-workers [4] describes the marked prognostic difference between N2 disease diagnosed at the time of mediastinoscopy and N2 disease determined at thoracotomy after a negative mediastinoscopy. Of 141 patients analyzed retrospectively, 79 had mediastinosopically positive nodes, whereas 62 patients had nodes that were negative at mediastinoscopy but positive at thoracotomy. Survival at 5 years was 9% in the former group versus 24% in the latter. Similar results have been noted by other groups [5, 6].

In addition to TNM staging, a number of other factors are relevant in evaluating the results of clinical trials in stage III NSCLC and determining the applicability of these trials to the general patient population. Two important and interrelated prognostic factors are weight loss and performance status [7, 8], which predict the response to and tolerance of therapy as well as overall prognosis. The Southwest Oncology Group (SWOG) analyzed 2,531 patients accrued to recent trials in extensive stage NSCLC and found that patients with good performance status (0–1) had improved 1-year survival (20% versus 9% p < 0.05) compared with similarly staged and treated patients with lower performance status (2–3). Similarly, a retrospective analysis of 590 patients with NSCLC enrolled in Eastern Cooperative Oncology Group trials demonstrated that the presence of weight loss reduced median survival from 20 weeks to 14 weeks (p < 0.01). In addition, pathologic factors reported to impact on response or survival in NSCLC, such as neuroendocrine differentiation [9], neovascularization [10], and DNA ploidy [11] have only occasionally been considered in study design or interpretation.

In a phase III trial in stage III disease randomizing patients to treatment with operation alone or neoadjuvant chemotherapy followed by operation, reported by Rosell and colleagues [12], the presence of K-ras mutations predicted a poor outcome, regardless of treatment assignment. The Rosell trial also evaluated DNA ploidy in tumor specimens. The findings, that 29% of patients receiving combined modality therapy (chemotherapy and operation) had aneuploid tumors versus 70% of patients treated with operation alone, might appear to be an inadvertent imbalance in variables. However, in 3 patients with adequate tissue available pretherapy, all changed from aneuploid to diploid after chemotherapy, indicating not only potential responsiveness to chemotherapy, but perhaps a posttreatment indicator of prognosis as well.

Implicit in a discussion of prognostic factors is the issue of appropriate staging. A major variable affecting interpretation of clinical trials in stage III NSCLC is the rigor with which patients are staged before study entry. Many trials have allocated patients to stage III based solely on computed tomography criteria. However, at this time computed tomography scanning remains an inexact method of staging or restaging NSCLC. The Radiologic Diagnostic Oncology Group evaluated 170 patients in a prospective multicenter trial. The sensitivity of computed tomographic scanning in distinguishing T3–4 from T0–2 was only 63% with a specificity of 84%. N2 or N3 disease could only be detected with a sensitivity of 52%. Magnetic resonance imaging was somewhat better at determining mediastinal invasion, but not superior in determining nodal involvement [13]. In comparison, recent studies of the SWOG have required pathologic evidence of N2 or N3 involvement or unequivocal evidence of T4 status (eg, vertebral destruction) for entry into combined modality trials in NSCLC.

No existing trial considers all available prognostic and staging factors, and in reality, new factors may become evident as current trials are being conducted. Nevertheless, careful consideration of study design and staging methods is essential in interpreting and comparing the results of recently conducted trials.


   Therapeutic Modalities
Top
 Footnotes
 Abstract
 Introduction
 Therapeutic Modalities
Study End Points
 Approach to Combined Modality...
 Future Directions
 Conclusions
 References
 
The goals of combined modality therapy in stage III NSCLC are improved local control and reduced distant metastases, theoretically the combination leading to increased long-term survival. Of the three modalities potentially used in the therapy of stage III NSCLC, operation, radiation therapy, and chemotherapy, the first two address the issue of local control, whereas the latter offers the potential for reduced distant metastases as well as cytoreductive and radiosensitizing effects on the primary tumor.

Operation
Surgical resection is used with curative intent in early stage NSCLC (stages I and II). Complete removal of tumor results in long-term survival of more than 70% in patients with T1 disease [14]. However, the curative potential of operation drops sharply with increasing T and N stage. Although surgical resection has been considered the ``standard of care'' for stage III NSCLC if it is technically feasible, this assessment lacks the support of prospective trials [15]. Whereas some reports indicate that almost 30% of patients with stage IIIA disease may be surgically cured, these series consist of highly selected individuals [16]. A more realistic estimate may be provided by two recent randomized trials comparing surgery alone to combined modality therapy in which 0% to 15% of the stage III patients who were felt to be candidates for primary operation were 2- to 3-year survivors [12, 17]. This figure is comparable to that reported for far less selected patients who are long-term survivors when treated with radiotherapy alone [18, 19].

Radiotherapy
Radiotherapy as a single modality has curative potential in early stage NSCLC. Doseretz and associates [20] demonstrated that of 152 technically resectable but medically inoperable patients, radiation alone produced 2- and 5-year survivals of 40% and 10%, respectively. This survival effect was most pronounced in low volume disease (T1) where 2-year survival was 55% compared with 20% and less than 5% for T2 and T3 disease. However, NSCLC is a systemic disease with occult micrometastases in the majority of patients. In recent phase III studies using a radiation alone control arm (eg, Dillman [18] and Le Chevalier [21] and their colleagues), only a small fraction of patients (less than 10%) are long-term survivors. In all series reported, distant failure remains the most common cause of death after local therapy with radiation alone.

In the United States accepted ``benchmark'' radiotherapy is 60 Gy delivered as 200 cGy/day in 30 fractions, as established by the Radiation Therapy Oncology Group (RTOG) in a randomized trial (RTOG 73-01) two decades ago [22]. Although this radiation dose schedule remains standard, it should be noted that in good prognosis, low volume stage III disease, higher doses (more than 65 Gy) have been associated with improved outcome [20].

Chemotherapy
To understand the emerging role of chemotherapy in combined modality treatment, it is instructive to first examine the current status of chemotherapy in metastatic (stage IV) disease. The usefulness of chemotherapy in stage IV NSCLC has been the subject of much debate [23]. Only recently, with the advent of cisplatin (cis-diamminedichloroplatinum)-based regimens, have randomized studies demonstrated a survival advantage of chemotherapy over supportive care alone (BSC). Although a number of randomized studies have been performed with this study design, only two have had an adequate sample size of stage IV patients to address appropriately this issue. Using a cisplatin-based regimen versus BSC, Cartei and co-workers [24] demonstrated both an advantage in median survival (8.5 versus 4.0 months, p < 0.0001), and more importantly, superior 1- and 2-year survivals (38.5% versus 12.0% and 9.6% versus 0%). In a similar fashion, the study by Rapp and colleagues [25] from the National Cancer Institute-Canada demonstrated a significant survival advantage for two different platinum-based regimens over BSC. The chemotherapy regimens were CAP (cyclophosphamide, 400 mg/m2; doxorubicin, 40 mg/m2; cisplatin, 40 mg/m2, every 4 weeks) and VP (vindesine, 3 mg/m2 weekly for 4 weeks, then every 2 weeks, and cisplatin, 120 mg/m2 day 1 and 29, then every 6 weeks). In 137 patients randomized to one of these three arms, median survival was 17 weeks for BSC, 24.7 weeks for CAP (p = 0.05 versus BSC) and 32.6 weeks for VP (p = 0.01 versus BSC).

These studies documenting a modest, but significant improvement in survival with cisplatin-based chemotherapy in metastatic NSCLC, take on added importance when placed in the context of the combined modality therapy of stage III disease. Chemotherapy has been used as a single modality in stage III NSCLC in a limited fashion, primarily in patients with more advanced local-regional disease (IIIB). In this setting (Table 2Go) cooperative group studies have uniformly documented an inverse correlation between tumor stage and response rate in NSCLC, with limited stage patients (primarily stage III) having a higher response rate to cisplatin-based chemotherapy compared with extensive stage patients (stage IV) [26–30].


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  		Table 2. . Chemotherapy Response in NSCLC: Limited Versus Extensive Diseasea
 
In addition to direct cytotoxic activity, chemotherapy also offers the potential to enhance the efficacy of radiotherapy. Chemotherapy and radiotherapy may interact in four ways: spatial cooperation, implying that disease not affected by one treatment is affected by the other; toxicity independence, in which two partially effective therapies with nonoverlapping toxicities are combined; protection of normal tissues from radiation damage, thereby improving the therapeutic index; and enhanced tumor response either through synergistic interaction or sensitization [31]. In NSCLC, cisplatin has been the drug most exploited in combined modality therapy with radiation [32]. The exact mechanisms of cisplatin interaction with radiation and the optimal dose schedule remain uncertain at this time.


   Study End Points
Top
 Footnotes
 Abstract
 Introduction
 Therapeutic Modalities
 Study End Points
Approach to Combined Modality...
 Future Directions
 Conclusions
 References
 
Prospective determination of appropriate study end points is crucial in the design and interpretation of clinical trials. Typical end points used in combined modality trials of stage III NSCLC are tumor response, resectability (if a surgical arm is included), median survival, and overall survival at 2 to 3 years. Despite recent success in standardizing the definition of these variables, they remain subject to interpretation [33]. For example, trials of neoadjuvant chemotherapy and radiotherapy have consistently demonstrated a poor correlation of clinical response as determined by computed tomography scanning with subsequent pathologic response at the time of surgical resection. Pathologic complete responses have been documented in approximately 20% of patients in almost all trials, and are observed even in patients with a response category of stable disease by computed tomography scanning. In SWOG 8805, a study designed to determine the feasibility of trimodality therapy in a cooperative group setting, there were 26 patients with computed tomography criteria for stable disease after induction chemoradiotherapy. At time of resection, 12 had either no residual tumor or microscopic foci only [34]. All of these patients were able to undergo complete tumor resection.

Resectability, although a focal point of analysis in trials of neoadjuvant therapy, may or may not predict long- term survival. Most such combined modality trials report 70+% rates of resectability (eg, 80% to 85% in SWOG 8805, 85% in the study by Rosell and colleagues). However, the most consistent predictor of prolonged survival is a pathologic complete response in the primary tumor and mediastinal lymph nodes. In SWOG 8805, patients found to have pathologically negative mediastinal nodes at the time of surgical resection had three times the median survival of those with residual involved nodes (median, 30 versus 9 months; 3-year survival, 41% versus 11%, p = 0.003) [34].


   Approach to Combined Modality Therapy
Top
 Footnotes
 Abstract
 Introduction
 Therapeutic Modalities
 Study End Points
 Approach to Combined Modality...
Future Directions
 Conclusions
 References
 
There are a number of different ways in which chemotherapy, radiation, and operation could be combined in the treatment of stage III NSCLC, each with potential advantages and disadvantages. For the purpose of discussion, we will divide combined modality approaches into two broad categories: (1) definitive chemotherapy and radiotherapy (nonsurgical combined modality therapy) and (2) neoadjuvant (induction) chemotherapy with or without radiotherapy followed by surgical resection. A third approach, adjuvant (postoperative) chemotherapy with or without radiotherapy, will not be considered in this review.

Nonsurgical Combined Modality Therapy
The theoretical advantages of combining chemotherapy and radiotherapy are clear. Appropriately delivered radiotherapy is a relatively effective means of achieving local control of disease in the chest, may possibly substitute for surgical resection, and has demonstrated curative potential. Chemotherapy offers the potential of reducing distant micrometastases, cytoreduction of local disease, and radiosensitizing effects.

Three approaches to combining chemotherapy and radiation have been investigated: sequential, concurrent, and alternating. Sequential or protochemotherapy completes administration of chemotherapy before radiotherapy. This approach avoids direct overlapping toxicities, therefore full doses of both modalities may be used, but loses the potential for chemotherapeutic radiosensitization. In addition, the duration of therapy is prolonged. Concurrent therapy optimizes both the radiosensitizing and local cytoreductive potential of chemotherapy but increases the risk of overlapping toxicity. Although there is no delay in use of either modality, concurrent therapy may preclude delivery of an optimal dose of either modality because of enhanced toxicity. Alternating radiotherapy and chemotherapy, similar to concurrent therapy, provides early use of both modalities and theoretically reduces toxicity by allowing time for normal tissue recovery. In older alternating programs, radiotherapy was potentially less effective due to delivery by a split course, but so-called integrated alternating approaches may alleviate this concern by a rapid alternation sequence [35].

Of the three methods of delivering chemoradiotherapy, sequentially administered chemotherapy and radiotherapy has been most extensively studied to date, with a number of mature phase III trials reported comparing this approach to radiotherapy alone (Table 3Go) [18, 19, 21, 36–42]. At first glance, the results of these studies appear inconclusive, with some trials showing improved survival with combined modality therapy and others showing no benefit. However, possible explanations emerge from closer evaluation. Some trials, (ie, Gregor) have had an inadequate sample size to address this question. In other trials, non-cisplatin-containing regimens or those with relatively low doses of cisplatin, have proven ineffective. In comparison, three studies with higher doses of cisplatin and adequate statistical power resulted in improved survival compared with radiotherapy alone. The study by Dillman and colleagues [41] from the Cancer and Leukemia Group B is particularly instructive. A limited course of chemotherapy (5 weeks, cisplatin 100 mg/m2 on weeks 1 and 5 and vinblastine 5 mg/m2 for weeks 1 through 5) followed by radiotherapy, 60 Gy/30 fractions was compared with the same radiotherapy alone in 155 stage III patients with good performance status (0–1) and minimal weight loss (less than 5%). Although median survival was modestly improved (13.8 versus 9.7 months, p = 0.0066) a doubling of survival at 2 years (26% versus 13%) was observed with a minimum of 5 years of follow-up [18, 41]. Because of early closure and a large number of early deaths in the radiation alone arm, concerns regarding the adequacy of the final sample size have been raised. However, a landmark analysis using 150 days as the point of departure still demonstrates improved survival for the combined modality arm. In addition, a subsequent intergroup trial has now reported confirmatory results [19]. This trial (RTOG 8808) had a similar design in terms of patient selection factors and the study arms for radiotherapy alone and chemoradiotherapy. A third arm evaluated the role of hyperfractionated radiotherapy. In the preliminary report of the intergroup study, median survival in the chemoradiotherapy arm (13.8 months) was significantly superior to the two radiotherapy arms (11.4 and 12.3 months) (log rank, p = 0.03).


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  		Table 3. . Phase III Trials: Induction Chemotherapy and Radiotherapy Versus Radiotherapy Alone
 
A French study in stage III disease by Le Chevalier and co-workers [40] compared a control arm of radiotherapy alone (65 Gy in 26 fractions) to three monthly cycles of vindesine 1.5 mg/m2 days 1 and 2, lomustine 50 mg/m2 day 2 and 25 mg/m2 day 3, and cisplatin 100 mg/m2 day 2 and cyclophosphamide 200 mg/m2 days 2 to 4 followed by the same radiotherapy. With 61 months median follow-up, survival was superior in patients receiving the combined modality therapy (p < 0.02). At 3 years, 12% of patients treated with chemotherapy were alive versus 4% of those treated with radiotherapy alone [21, 40]. In contrast to the Cancer and Leukemia Group B study, this trial demonstrated a significant difference in the pattern of tumor recurrence. In this French study, the rate of distant metastasis was significantly lower in the combined modality group than in the radiotherapy alone group (p < 0.001). In addition, using rigorous restaging, which included bronchoscopy, this trial showed less than 20% of patients on either treatment arm maintained local control at 1 year. Parenthetically, this study also demonstrates the problem of early reporting and the importance of continued follow-up. Although the study of Le Chevalier was initially reported as negative, the survival advantage for chemotherapy/radiotherapy first emerged at 3 years of follow-up.

Table 4Go provides the results of four recently reported phase III trials of concurrent cisplatin-radiotherapy versus radiotherapy alone [42–45]. The hypothesis that improved local control from chemoradiosensitization could result in improved survival is supported by a study from the European Organization for the Research and Treatment of Cancer, reported by Schaake-Koning and colleagues [42]. This study enrolled 331 patients from 20 European centers. Most patients had stage III NSCLC, but a significant fraction had more localized, medically inoperable disease. Three treatment arms were evaluated. A split course radiotherapy arm consisted of (55 Gy) delivered as 3.5 Gy/day over 10 days followed by a 3- to 4-week rest period and then 2.5 Gy/day over 10 days. A second arm delivered the same radiotherapy with concomitant weekly cisplatin at a dose of 30 mg/m2 per week, and a third arm consisted of the same radiation dose schedule plus daily cisplatin (6 mg/m2) on the days of radiotherapy. Both cisplatin-containing arms showed superior results to radiation alone, with a statistically significant survival advantage in favor of daily cisplatin over radiotherapy alone (p = 0.009). Two-year survivals were 13%, 19%, and 26% for radiotherapy alone, weekly cisplatin, and the daily cisplatin arms, respectively. Of interest, the survival advantage with cisplatin resulted entirely from improved local control, with a 2-year freedom from local recurrence of 19% in the radiotherapy alone arm versus 30% in the chemotherapy arms. There was no difference in time to development of distant metastasis. The results raise an intriguing point with regard to the therapeutic intent of chemotherapy in combined modality therapy approaches. It would appear that low-dose daily cisplatin in this study functioned primarily as a radiosensitizer, resulting in improved local control, and was relatively ineffective against occult systemic disease. Conversely, higher doses of cisplatin (ie, 60 to 100 mg/m2) as used in the LeChevalier study, may be more effective in eradicating distant micrometastases.


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  		Table 4. . Phase III Trials: Concurrent Chemotherapy/Radiotherapy Versus Radiotherapy Alone
 
Three other randomized trials have not demonstrated an advantage of concurrent chemoradiotherapy over radiotherapy alone. In a similar trial design to the European Organization for the Research and Treatment of Cancer study, Trovo compared combined modality therapy with daily cisplatin at a dose of 6 mg/m2 with concurrent radiotherapy (45 Gy) to radiotherapy alone. Although there was little difference in either response rate or median survival, the radiotherapy total dose (45 Gy) was suboptimal by current standards [44]. Both the studies by Soresi [43] and Blanke [45] and their colleagues demonstrate a trend toward improvement with chemotherapy, although this did achieve statistical significance.

An alternative approach to concurrent therapy is so-called integrated alternating strategy in which cytoreductive doses of chemotherapy are administered between cycles of radiotherapy. This approach is feasible and promising, a phase III trial is underway in Europe [46].

A recent study by Kubota and co-workers [47] addresses the specific role of radiotherapy in the non-surgical combined modality treatment of locally advanced NSCLC, a legitimate question given the poor degree of local control reported with current chemoradiotherapy regimens. Unfortunately, this study was designed with multiple randomizations, resulting in relatively small numbers of patients for subset analysis. Despite similar median survival times between chemotherapy alone and chemoradiotherapy (447 versus 461 days), the long-term survival of the patient groups was markedly different, with 35.5% versus 9.4% (p = 0.016) and 29.0% versus 3.1% (p = 0.0049) 2- and 3-year survival for the chemoradiotherapy versus chemotherapy groups. This study suggests that radiotherapy plays an important role in determining outcome from combined modality therapy.

Neoadjuvant Chemotherapy With and Without Radiotherapy Followed by Surgical Resection
This concept was initially explored in a number of single institution pilot studies to determine feasibility. Additional goals of these studies were to devise chemotherapy programs that would produce a high response rate, including clinical complete response, with few tumor progressions occurring preoperatively. This cytoreductive therapy was intended to increase the resectability rate of patients with stage III NSCLC, with little increase in operative or postoperative morbidity or mortality. If proved successful, this approach would result in improved local control, improved disease-free survival, and ultimately, improved long-term survival.

Table 5Go illustrates several recent phase II studies of neoadjuvant chemotherapy with or without radiation before surgical resection [48–55]. In all studies, the chemotherapeutic regimen used was cisplatin-based. Although the results of these pilot studies should not be overinterpreted, it is clear that cisplatin chemotherapy, with or without radiation therapy, can result in a high response rate and high degree of resectability (complete resection, 30% to 70%). In most studies concurrent radiation therapy has been delivered preoperatively, to a total dose of 30 to 45 Gy. Some investigators have attributed increased difficulty of resection and perioperative complications to these chemoradiotherapy programs [56]. Nevertheless, the feasibility of this approach was amply demonstrated in a recent multicenter SWOG trial. Albain and associates [34] reporting for SWOG, combined cisplatin and etoposide with concurrent radiotherapy to 45 Gy. More than one-third of patients had pathologically determined stage IIIB disease, making this study unique. A complete resection rate of 73% and 21% pathologic complete remissions was achieved. There was no difference in resectability or in long-term survival between stage IIIA and IIIB. Early perioperative morbidity and mortality were low, however, there were 8% late pulmonary deaths and 12% of patients with persistent debility after operation or boost radiotherapy.


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  		Table 5. . Neoadjuvant Chemotherapy/Radiotherapy Followed by Surgical Resection
 
Two phase III trials evaluating surgical resection with or without neoadjuvant chemotherapy have been reported (Table 6Go). The studies of Roth [17] and Rosell [12] and their colleagues both demonstrate increased survival with the use of neoadjuvant chemotherapy before surgical resection, compared with operation alone. Unfortunately, both trials consist of relatively small numbers of patients. In the Roth study, 60 patients with pathologically determined N2 disease or unequivocal T3 disease were randomized to receive either operation alone or induction chemotherapy with three cycles of cyclophosphamide 500 mg/m2 day 1, etoposide 100 mg/m2 days 1 to 3, and cisplatin 100 mg/m2 followed by operation. Selected patients in both groups received postoperative radiotherapy. Median survival was 11 months for the operation alone group versus 64 months for the combined modality group (p = 0.008, log rank), with 3-year survivals of 15% versus 56%, respectively.


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  		Table 6. . Operation Alone Versus Neoadjuvant Chemotherapy Followed by Operation in Stage III NSCLC
 
In a similar study design, Rosell and colleagues [12] randomized 60 patients to either surgical resection followed by chest radiotherapy (50 Gy) or three courses of induction chemotherapy with mitomycin 6 mg/m2, ifosfamide 3 g/m2, and cisplatin 50 mg/m2 followed by operation and radiotherapy. There was a highly significant improvement in disease-free survival and overall survival in the chemotherapy arm, resulting in early closure of the trial. Median survival was 26 months in the trimodality arm versus 8 months with operation and radiation (p < 0.001). Most importantly, at 2 years, survival was 23% in the chemotherapy group versus 0% in the operation and radiation group. Although the results of these trials are provocative, they should not be over- interpreted, due to the small number and selected nature of patients treated. To address directly the impact of surgical resection on both efficacy and toxicity of neoadjuvant therapy, an intergroup study has now been initiated comparing the SWOG approach of neoadjuvant cisplatin/VP-16/radiation followed by surgical resection to definitive cisplatin/VP-16/radiation alone.

A trial by Fleck and associates [57] addresses the important question of whether radiation therapy provides additive benefit to chemotherapy and operation. In this study, 96 patients were randomized to either neoadjuvant chemotherapy (cisplatin 100 mg/m2 days 1 and 29 and 5-fluorouracil on days 1 to 4 and 29 to 32) or chemoradiotherapy (three cycles of 21 days, cisplatin 100 mg/m2, mitomycin C 8 mg/m2, and vinblastine 4.5 mg/m2 every other week and radiation to 30 Gy) with an additional 30 Gy postoperatively if residual disease was present before planned surgical resection in both arms of the study. Although only preliminary results have been reported to date, there was a marked improvement in resectability and freedom from progression in the arm delivering radiotherapy in addition to chemotherapy.

Although the results from these surgical studies are encouraging, 2-year survival data are remarkably similar to the results of studies using definitive chemoradiotherapy without operation. This is especially evident when one considers that surgical trials almost invariably involve selection bias for healthier patients. Although the Fleck trial addresses directly the need for radiation therapy in addition to neoadjuvant chemotherapy, the importance of this issue mandates a confirmatory study.


   Future Directions
Top
 Footnotes
 Abstract
 Introduction
 Therapeutic Modalities
 Study End Points
 Approach to Combined Modality...
 Future Directions
Conclusions
 References
 
Although several studies of combined modality therapy report modest improvements in survival, an optimal treatment approach to stage III NSCLC has yet to be identified. The results of recent studies define a new standard of care in which patients with minimal weight loss and good performance status can be treated with combined modality therapy, with prospects of long-term survival in 20% to 30%. Nevertheless, the great majority of stage III patients still die of recurrent disease, mandating the need for continued clinical research studies evaluating new therapeutic approaches.

Refinement of surgical techniques including mediastinal lymph node mapping and the use of video-assisted thorocoscopy has added to accurate pretreatment and posttreatment staging. New radiation techniques such as hyperfractionated or accelerated schedules merit further exploration in trials of concurrent chemotherapy. In addition, the use of three-dimensional conformal therapy offers the possibility of improved local control [58]. This technique allows for higher radiation dosing (more than 70 Gy) of the tumor, while sparing surrounding normal lung [59]. Current techniques are estimated to underdose approximately 20% of known disease. A three-dimensional conformal therapy dose escalation trial has been implemented recently by the RTOG, and will assist in defining accurately the optimal radiation dose for achieving local control in stage III NSCLC.

Systemic recurrence remains the major cause of treatment failure. Therefore, new and better chemotherapy agents or improved utilization of current agents remains a priority in clinical trials in stage III disease. Fortunately, there are now several new agents undergoing evaluation that demonstrate reproducible single agent activity in NSCLC, some with novel mechanisms of action and toxicities that do not overlap with cisplatin (Table 7Go). In addition, some of these agents have demonstrated synergistic antitumor effects with radiation [60]. Determining the contribution of these new agents in combined modality therapy will require carefully designed and conducted clinical trials, and their use in this setting should be considered investigational at the present time.


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  		Table 7. . New Agents in Advanced NSCLC: Results of Phase II Trials
 

   Conclusions
Top
 Footnotes
 Abstract
 Introduction
 Therapeutic Modalities
 Study End Points
 Approach to Combined Modality...
 Future Directions
 Conclusions
References
 
Despite more than two decades of clinical research, stage III NSCLC remains a lethal disease in the majority of patients. Nevertheless, therapeutic nihilism is no longer justified. Several recent large, well-executed phase III trials have demonstrated improved long-term survival with the use of combined modality therapy compared with radiotherapy or operation alone. The inclusion of cisplatin-based chemotherapy is a common denominator of all successful approaches reported to date. However, the optimal combination and sequencing of modalities remains undefined, and may well be different for subsets of stage III disease. If possible, any patient with locally advanced NSCLC should be entered on a clinical trial. If a trial is unavailable, or the patient is ineligible or unwilling to participate, Figure 1Go outlines a reasonable approach to the various subsets of stage III NSCLC based on currently available data. Continued accrual of patients to ongoing clinical trials is essential if further progress is to be made.



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  		Fig 1. . Nonprotocol therapy for patients with stage III non-small cell lung cancer (NSCLC). (Chemo = chemotherapy; ECOG = Eastern Cooperative Oncology Group; PS = performance status; RX = treatment; wt = weight; XRT = radiation therapy.)

 


   Footnotes
Top
 Footnotes
Abstract
 Introduction
 Therapeutic Modalities
 Study End Points
 Approach to Combined Modality...
 Future Directions
 Conclusions
 References
 
Address reprint requests to Dr Edelman, Division of Hematology/Oncology, University of California, Davis, VA Outpatient Clinic (111-H), 150 Muir Rd, Martinez, CA 94553.


   References
Top
 Footnotes
 Abstract
 Introduction
 Therapeutic Modalities
 Study End Points
 Approach to Combined Modality...
 Future Directions
 Conclusions
 References
 

  1. Wingo PA, Tong T, Bolden S. Cancer statistics, 1995. Ca 1995;45:8–30.
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