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Non-Small Cell Lung Cancer: Prognostic Factors in Patients Treated with Surgery and Postoperative Radiation Therapy¹

¹ From the Department of Radiation Oncology (J.H.L., M.M., S.M.H., M.G.M., W.G.M.) and the Divisions of Thoracic Surgery (L.R.K., J.S.F.) and Hematology/Oncology (S.M.H.), University of Pennsylvania Medical Center, 3400 Spruce St, 2 Donner, Philadelphia, PA 19104. From the 1998 RSNA scientific assembly. Received November 30, 1998; revision requested January 14, 1999; revision received March 1; accepted July 1. Address reprint requests to M.M. (e-mail: machtay@xrt.upenn.edu).

	Abstract

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PURPOSE: To determine survival outcomes, to identify adverse prognostic factors for relapse, and to compare American Joint Commission on Cancer (AJCC) staging systems in patients with non–small cell lung cancer (NSCLC) treated with surgery and postoperative radiation therapy.

MATERIALS AND METHODS: Between 1980 and 1995, 211 patients with NSCLC underwent surgery and postoperative radiation therapy. Surgery consisted of wedge resection (12.5%), lobectomy (67.8%), or pneumonectomy (19.7%). Pathologic stages (1992 AJCC) included I (n = 22), II (n = 70), IIIA (n = 104), and IIIB (n = 12). Indications for radiation therapy included compromised margins (n = 81) and/or positive mediastinal nodes (n = 55). Prognostic factors were identified by using univariate and multivariate models.

RESULTS: Overall 3-year survival for patients with stage I, II, and IIIA cancer was 58.9%, 44.1%, and 43.2%, respectively. Older age (P = .008), male sex (P = .021), large primary tumor (P = .004), and multiple positive mediastinal nodes (P = .046) were associated with worse rates of survival. Actuarial risk of local-regional relapse (36 patients) was 21.4% at 3 years. In a multivariate model, use of wedge resection (P = .001), positive margins (P = .010), and larger pathologic tumor (P = .059) were risk factors for local-regional recurrence. Actuarial rate of distant failure was 55.2% at 3 years.

CONCLUSION: Local-regional control can be achieved with surgery and radiation therapy in approximately 80% of patients; however, the rate of distant metastasis remains unacceptably high. Other variables, such as multiple positive nodes, may serve to identify patients at higher risk for relapse and poorer survival. Methods for improving treatment outcomes in these patients should be pursued.

Index terms: Lung neoplasms, 60.321 • Lung neoplasms, surgery, 60.321, 60.45 • Lung neoplasms, therapeutic radiology, 60.321, 60.1299

	Introduction

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Approximately 140,000 cases of non–small cell lung cancer (NSCLC) are diagnosed annually in the United States (1). The vast majority of patients with NSCLC will ultimately die of the disease, which makes lung cancer the leading cause of cancer deaths. Only one-third of patients are candidates for definitive surgical management (2). Although complete resection in patients with early disease can be curative, patients with positive nodes or advanced primary lesions fare less well; often, relapse occurs locally or distantly (3). Patients in the latter group may be candidates for adjuvant local or systemic therapies.

In an attempt to improve disease control after resection for NSCLC, radiation therapy has been administered in the adjuvant setting for high-risk patients (4–11). Findings from many of these studies demonstrate improved local-regional control and improved survival, when compared with historical findings or findings in contemporary untreated patients. Despite the evaluation of postoperative radiation therapy in several randomized trials (12–15), this adjuvant treatment remains controversial and incompletely evaluated (16–18). The lack of clear survival benefit and the potential long-term pulmonary toxic effects of postoperative radiation therapy place this regimen in question. The use of postoperative radiation therapy is often dependent on the practice patterns of referring surgeons and radiation oncologists.

Investigators in a recently published meta-analysis (19) sought to clarify this issue by evaluating all known randomized trials in which postoperative radiation therapy for NSCLC was evaluated. The investigators found no survival benefit for patients with stage III cancer and found possibly worse rates of survival in patients with earlier-stage cancers. These results may not reflect the experience in the United States, as only 11% of the patient data were derived from U.S. trials.

Using linear-accelerator–based treatment facilities, we administered post-operative radiation therapy in the adjuvant setting to patients at higher risk. The objectives of this study were to determine survival outcomes, to identify prognostic factors for relapse and death, and to compare American Joint Commission on Cancer (AJCC) staging systems (1992 vs 1997) in patients with NSCLC treated with surgery and postoperative radiation therapy.

	MATERIALS AND METHODS

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Between 1980 and 1995, 211 patients with a histologic diagnosis of NSCLC underwent surgery with curative intent and postoperative radiation therapy administered at our institution. Charts were retrospectively reviewed (by M.M., J.H.L.) for patient-, tumor-, and treatment-related factors that may have influenced prognosis. One hundred twenty-seven of the cohort were men, and 84 were women. The median age of treated patients was 63.8 years (age range, 27–89 years). Sixty-nine (36%) patients had squamous cell cancers.

Cancer in patients had been staged by using clinical and radiographic information and had been assigned a clinical AJCC stage based on 1992 and 1997 definitions (20,21). The majority (122 patients [58%]) of patients had stage I disease, 20 (9%) patients had stage II disease, and 44 (21%) patients had stage IIIA disease, according to 1992 definitions. Only 18 (9%) patients had clinically evident mediastinal adenopathy, and four of these patients received preoperative chemotherapy in this setting. No patients with supraclavicular adenopathy, contralateral mediastinal nodes, or clinically evident T4 primary tumors were included in this analysis. Clinical and histologic characteristics of the patients are listed in Table 1.

After surgery, the stage grouping worsened compared with the clinical stage grouping (in 114 patients [54%]); the stage improved in only one patient. All patients with pathologic stage IIIB cancer were assigned this stage on the basis of a T4 primary tumor and not on the basis of N3 nodal disease. Pathologic features and staging information are shown in Table 2.

Radiation therapy consisted of treatment with linear accelerator-based megavoltage photons, with a median dose of 5,600 cGy (range, 2,160-6,660 cGy) in 180–200-cGy daily fractions. Prescribed doses were not corrected for lung inhomogeneity. Two hundred three (96.2%) of the patients received at least 4,500 cGy.

Patients were treated in anteroposterior-posteroanterior fashion in the mediastinum and ipsilateral hilum. For locally advanced tumors, the region of the primary tumor was included in the treatment field. The extent of additional regional coverage (ie, supraclavicular fossa, lower mediastinum) was not standardized, but rather, it was dependent on the practice of the treating radiation oncologist. Doses above 4,500 cGy were delivered through oblique fields and were not delivered with the addition of a midline block or opposed lateral fields. Chemotherapy was administered preoperatively in four patients, postoperatively in eight patients, and both preoperatively and postoperatively in two additional patients.

Outcome measures included toxic effects due to radiation, local-regional failure, distant dissemination, and overall survival. Clinically important pulmonary (grade 2 or higher) or other thoracic (grade 3 or higher) toxic effects were recorded. Local-regional failure was defined as radiographic or pathologic documentation of recurrence within the primary tumor bed, ipsilateral hilum, or mediastinum. Distant dissemination was defined as clinical or radiologic evidence of M1 disease, according to the 1997 AJCC definition (21). Time to failure was assessed from the date of surgical resection. Survival and relapse rates were calculated by using the Kaplan-Meier product-limit method.

Prognostic factors for local-regional recurrence, distant metastasis, and overall survival were identified by using univariate and multivariate models. We assessed whether the 1992 staging definitions or the 1997 staging definitions could be used to better predict survival, particularly among patients with stage II or stage III disease. The effect of age was assessed as a covariate and stratification variable; patients were divided into the following four age groups: 50 years or younger, 50–60 years, 60–70 years, and older than 70 years.

	RESULTS

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Overall Survival
Median follow-up was 25 months for all patients and was 39.5 months for surviving patients. Median survival for the entire cohort was 32 months. Overall 2-year, 3-year, and 5-year survival was 61.3%, 45.7%, and 34.2%, respectively. Survival for patients with pathologic stages I, II, IIIA, or IIIB was 58.9.%, 44.1%, 43.2%, or 45.0%, respectively, at 3 years. With the 1997 AJCC system, the stage grouping in 37 patients with T3N0 disease was reclassified as stage II, and patients experienced survival similar to or better than that of other patients with stage II disease (47.9%). The difference in survival between patients with 1997 AJCC stage II disease and those with stage IIIA disease was not statistically significant (46.1% vs 39.2%, P = .460). Survival by pathologic stage is shown in Figure 1.

View larger version (14K): [in this window] [in a new window]   Figure 1. Plot depicts overall survival by pathologic stage according to 1992 AJCC staging definitions, as determined at actuarial analysis. Number of patients at risk are shown above each time interval. Survival for patients with stage IIIA(N2) cancer is 29% at 5 years. Numbers in parentheses are numbers of patients.

View larger version (10K): [in this window] [in a new window]   Figure 2. Plot depicts local-regional control for all patients, as determined at actuarial analysis. Number of patients at risk are shown above each time interval. Local-regional control at 5 years is 74%.

View larger version (14K): [in this window] [in a new window]   Figure 3. Plot depicts local-regional control by type of surgical resection, as determined at actuarial analysis. Data from patients undergoing wedge resection show that they are at significantly higher risk for recurrence. Numbers in parentheses are numbers of patients.

View larger version (14K): [in this window] [in a new window]   Figure 4. Plot depicts local-regional control by margin status, as determined at actuarial analysis. Data from patients with positive margins show that they are at significantly higher risk for recurrence. Numbers in parentheses are numbers of patients.

View larger version (11K): [in this window] [in a new window]   Figure 5. Plot depicts risk of distant dissemination for all patients, as determined at actuarial analysis. Number of patients at risk are shown above each time interval.

Toxic Effects
Twenty (9%) of the patients experienced clinically important subacute or late toxic effects due to radiation therapy. Five patients developed grade 3 or higher esophageal stricture. Seven patients developed grade 2 or higher symptomatic pneumonitis. Two patients had bone or rib fractures, and six patients had other unspecified toxic effects. There were no treatment-related deaths.

	DISCUSSION

TOP Abstract Introduction MATERIALS AND METHODS RESULTS DISCUSSION References

 
The justification for postoperative radiation therapy after surgery for advanced NSCLC lies in the suboptimal local control achieved with surgery alone, in the highly lethal nature of intrathoracic relapse, and in the potential risk of secondary dissemination in patients with active local disease. Evidence from several nonrandomized studies (4–11,22) suggests that postoperative radiation therapy can improve both local-regional control and overall survival in high-risk patients, as summarized in Table 7.

Several high-risk features have been identified for local relapse, distant dissemination, and poorer survival. The use of wedge resection was associated with a high rate of local failure despite the administration of postoperative radiation therapy. The presence of positive margins also resulted in a local-regional failure rate of 33%, which is greater than the 13% failure rate reported by the Lung Cancer Study Group (26) for incompletely resected cases. The presence of multiple positive nodes was associated with increased risk of distant dissemination and poorer survival. The negative influence of multiple positive mediastinal nodes or multiple levels of mediastinal node involvement has been described previously (10,12) and was confirmed in this series.

The survival outcomes for patients with stage I or II cancer are somewhat disappointing, when compared with the expected results in these patients (27). One may infer from the use of adjuvant radiation therapy that these patients represent a group at somewhat higher risk. In this series, over 60% of patients with stage I disease had close or positive margins, and the majority of patients with stage II disease had no mediastinal nodal staging. With formal mediastinal dissection, it is possible that disease in a substantial proportion of patients with only positive hilar nodes may have advanced to stage IIIA disease, which may explain the close survival results between these two groups. By using the 1997 AJCC staging system (21), there was better separation between the groups with stage II or stage IIIA cancer, although with the current number of patients, this difference was not statistically significant.

Arguments against routine postoperative radiation therapy include the propensity for systemic dissemination regardless of local measures, the added toxic effects of pulmonary radiation therapy, and the lack of a survival benefit achieved in randomized trials (12–15,28). Table 8 summarizes the results from selected published randomized trials. In the widely quoted Lung Cancer Study Group trial (13), the advantage in local-regional control did not translate to improved survival for carefully staged patients with squamous cell carcinoma. In other trials, worse survival was reported in the patients who had undergone irradiation (15,28). Pulmonary toxic effects from irradiation may explain some of the negative findings; in our series, there were few clinically evident complications and no treatment-related deaths.

Several issues surrounding this analysis may limit its validity. As shown in Table 9, the PORT study (19) included a substantial number of patients who underwent complete resection for stage I or II cancer and for whom routine adjuvant radiation therapy would have offered little advantage and was not advised. Also, many patients underwent treatment with low-energy cobalt 60 machines, which are rarely available in the United States and which may have contributed to high rates of complication and treatment-related mortality after lung surgery (30). Despite the more advanced stage disease in our population and despite the greater number of risk factors, the 2-year survival in our cohort exceeded that determined by the PORT investigators (Table 9).

There are several limitations of this study, including those inherent to any retrospective review. Our population was fairly heterogeneous, as was the extent of surgical staging and the type of surgical resection performed. The results reported here may reflect the outcomes that may be expected outside the rigor of clinical trials, such as those conducted by the Lung Cancer Study Group. Unfortunately, the lack of strict mediastinal staging also limited the ability to analyze outcomes that were based on these important prognostic markers, as shown by Sawyer and colleagues (37). In addition, this study lacked an appropriate control group. Without a protocol for randomization, a truly matched cohort is difficult to obtain, as multiple factors are often considered after surgery (ie, completeness of resection, patient's performance status) that may or may not compel physicians to refer patients for adjuvant therapy.

In conclusion, we have demonstrated that local-regional control can be achieved in approximately 80% of patients who undergo surgery and postoperative radiation therapy, despite a number of high-risk factors. However, the rate of distant metastasis remains discouragingly high. Variables other than AJCC stage, such as multiple positive nodes, have been identified as risk factors for poorer survival and distant relapse. Methods for improving local-regional and distant control in these patients at high risk for recurrence should be pursued. Identification of patients at higher risk for recurrence and/or death, use of more sophisticated targeting systems at radiation therapy, and attention to radiation therapeutic technique may further improve the therapeutic ratio for postoperative radiation therapy.

	Footnotes

 
Abbreviations: AJCC = American Joint Commission on Cancer NSCLC = non–small cell lung cancer

Author contributions: Guarantor of integrity of entire study, W.G.M.; study concepts, M.M., L.R.K., J.S.F., S.M.H., M.G.M., W.G.M.; study design, M.M.; definition of intellectual content, M.M.; literature research, J.H.L., M.M.; clinical studies, M.M., L.R.K., J.S.F.; data acquisition, M.M., M.G.M.; data analysis, M.M.; statistical analysis, J.H.L.; manuscript preparation, J.H.L.; manuscript editing, J.H.L., M.M.; manuscript review, M.M., L.R.K., J.S.F., S.M.H., M.G.M., W.G.M.

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