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(Chest. 2005;128:1461-1467.)
© 2005 American College of Chest Physicians

Radiation Therapy for the Treatment of Unresected Stage I-II Non-small Cell Lung Cancer*

Juan P. Wisnivesky, MD, MPH; Marcelo Bonomi, MD; Claudia Henschke, PhD, MD, FCCP; Michael Iannuzzi, MD, FCCP and Thomas McGinn, MD, MPH

* From the Division of General Internal Medicine (Drs. Wisnivesky and McGinn) and Pulmonary, Critical Care, and Sleep Medicine (Dr. Iannuzzi), Mount Sinai School of Medicine, New York, NY; the Department of Radiation Oncology (Dr. Bonomi), Instituto Angel H. Roffo, Universidad de Buenos Aires, Buenos Aires, Argentina; and the Department of Radiology (Dr. Henschke), New York-Presbyterian Hospital-Weill Cornell Medical Center, New York, NY.

Correspondence to: Juan P. Wisnivesky, MD, MPH, Department of Medicine, Mount Sinai School of Medicine, One Gustave L. Levy Pl, Box 1087, New York, NY 10029; e-mail: juan.wisnivesky{at}mssm.edu


   Abstract
TOP
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
Study objectives: Radiotherapy is considered to be the standard treatment for patients with stage I or II non-small lung cancer who refuse surgery or who are not surgical candidates because of significant comorbidities. To determine whether radiotherapy benefits these patients, we compared the survival of those treated with radiation alone to those left untreated.

Methods: Using the Surveillance, Epidemiology, and End Results registry, we identified all patients in whom histologically confirmed, stage I and II non-small cell lung cancer had been diagnosed between 1988 and 2001. Among these patients, 4,357 did not undergo surgical resection. Kaplan-Meier survival curves were compared among patients who received and who did not receive radiation therapy. We used Cox regression analysis to evaluate the effect of radiation on survival after adjusting for potential confounders.

Results: The survival of patients with lung cancer who did not undergo resection and had been treated with radiation therapy was significantly better compared to the untreated patients (stage I cancer, p = 0.0001; stage II cancer, p = 0.001). The median survival time of patients with stage I disease who underwent radiotherapy was 21 months compared to 14 months for untreated patients. Stage II patients who received and did not receive radiation therapy had median survival times of 14 and 9 months, respectively. The survival of treated and untreated patients was not significantly different approximately 5 years after diagnosis (stage I disease, 15% vs 14%, respectively; stage II disease, 11% vs 10%, respectively). In multivariate analysis, radiation therapy was significantly associated with improved lung cancer survival after controlling for age, sex, race, and tumor histology.

Conclusions: These results suggest that radiotherapy is associated with improved survival in patients with unresected stage I or II non-small cell lung cancer. The observed improvement in median survival time was only 5 to 7 months, and radiotherapy did not offer the possibility of a cure.

Key Words: non-small cell lung cancer • radiation therapy • stage I-II • survival • unresected


   Introduction
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 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
Surgical resection is the most effective treatment for stage I and II non-small cell lung cancer,12 yet nearly 25% of these patients do not undergo surgery.3 Radiation therapy is generally used to treat these patients who, despite having resectable tumors, refuse surgery or have inoperable conditions due to medical reasons.1

The role of radiation therapy in the treatment of unresected stage I non-small cell lung carcinoma has been evaluated in several retrospective analyses4567891011121314151617181920 and summarized in two reviews.2122 For patients with unresected tumors, the prognosis is poor, with a 20% 5-year lung cancer survival rate (range, 13 to 39%). The majority of these studies, however, evaluated small numbers of patients, who often had been recruited from single tertiary centers, and used various radiation doses and fractions. Furthermore, these studies did not compare the survival outcomes of treated and untreated patients. Additionally, several of these studies were conducted in the 1980s and early 1990s, thus reflecting the efficacy of two-dimensionally planned radiotherapy using daily fractions of 1.8 to 2 Gy to a total dose of 60 to 66 Gy, rather than newer techniques such as three-dimensional conformal radiotherapy.2324 Since stage II cases constitute < 10% of the total number of patients with non-small cell lung cancer, much less is known about the outcomes and effectiveness of radiation therapy alone for these patients.2526 Using population-based cancer data, we compared the survival of stage I and II lung cancer patients treated with radiotherapy alone to a concurrent cohort of patients with a similar stage of disease who did not receive treatment.


   Materials and Methods
TOP
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
The Surveillance, Epidemiology, and End Results (SEER) program is a National Cancer Institute-funded database that has been collecting clinicopathologic data on all incident cancer cases in selected geographic areas of the United States since 1973. From the SEER registry 2004, we identified all cases of non-small cell lung cancer (tumor site codes 34.0 to 34.9 and International Classification of Diseases-Oncology-second revision, morphology codes 8010 to 8040, 8050 to 8076, 8140, 8143, 8250 to 8260, 8310, 8320, 8323, 8470 to 8490, and 8550 to 8573) that had been diagnosed in 1988 or later, as the histologic and staging classification in SEER had significantly changed.27 Among these cases, we narrowed the focus to microscopically confirmed primary cancers diagnosed prior to autopsy. There were 159,185 such cases.

Among these subjects, we identified cases of stage I and II cancer by the following American Joint Committee on Cancer28 criteria: T1 (noninvasive tumor of diameter ≤ 3 cm, without evidence of invasion more proximal than the lobar bronchus; SEER tumor extent code 10); T2 (tumor with any of the following features of size or extent: > 3 cm in dimension; involves main bronchus ≥ 2 cm distal to the carina; invades the visceral pleura; associated with atelectasis or obstructive pneumonitis that extends to the hilar region but does not involve the entire lung; SEER tumor extent code 20 and 40); T3 (tumor of any size that directly invades any of the following: chest wall; diaphragm, mediastinal pleura; parietal pericardium; or tumor in the main bronchus < 2 cm distal to the carina, but without involvement of the carina; or associated atelectasis or obstructive pneumonitis of the entire lung; SEER tumor extent codes 50 and 60); N0 (absence of lymph node metastasis; SEER lymph node code 0) N1 (metastasis to ipsilateral peribronchial and/or hilar, and intrapulmonary nodes; SEER lymph node code 1); and M0 (no distant metastasis; SEER tumor extension < 75). We found 30,790 stage I cases (T1–2N0M0) or stage II cases (T1–2N1M0 or T3N0M0).

Of these cases, 4,518 patients did not undergo surgical treatment. We excluded 127 patients due to inadequate data as to whether or not radiation therapy had been administered and 34 patients due to lack of information regarding the radiation method used, leaving a cohort of 4,357 patients. Case patients were classified as not having undergone resection if the SEER site-specific variable indicated that no surgical procedure (eg, local resection, segmentectomy, wedge resection, lobectomy, and partial or total pneumonectomy [SEER codes 10 to 70]) had been performed. Patients were classified as having received radiation therapy if the SEER radiation code indicated that the patient had undergone beam radiation (SEER radiation code 1).

Along with stage at diagnosis and treatment, the SEER registries also provide information about the patient’s age at diagnosis, sex, race, histology, and tumor size. Cancer site and morphology are coded in SEER according to the International Classification of Diseases for Oncology, Second Edition.29 The cause of death provided in the SEER registry is abstracted from the National Center for Health Statistics database of consolidated death certificates from Vital Statistics Office in each state.

Statistical Analysis
Differences in the distribution of sex, age category (eg, ≤ 65, 66 to 70, 71 to 75, and >75 years), race, stage distribution, histology, and tumor size distribution (eg, ≤ 15, 16 to 30, 31 to 45, and > 45 mm) between patients who received or did not receive radiation therapy were evaluated using the {chi}2 test. All reported p values were two-sided, and we used a significance level of 0.05.

The Kaplan-Meier method was used to estimate lung cancer-specific survival rates.3031 Due to existing comorbidity, the use of cancer-specific survival is more appropriate to adjust for other causes of death. To estimate cancer-specific survival rates, deaths attributed to causes other than lung cancer were treated as censored at the date of death under the assumption that deaths from the underlying cancer were independent of deaths from other causes. To assess the clinical impact of radiation therapy on lung cancer survival, we compared the survival of patients who received radiation therapy and did not receive radiation therapy using the log-rank statistic.

Several published studies491019 reported that the response to radiotherapy is dependent on tumor size. We used Cox regression to evaluate whether the effectiveness of radiation therapy varied according to tumor size. For this purpose, we fitted a model including variables indicating the tumor size category, a dummy variable indicating whether the patient received radiotherapy, and interaction terms. In this model, the interaction terms would have a p value of < 0.05 if the effect of radiation depended on tumor size. We use a similar approach to compare patient outcomes across different treatment periods. Consistent with the results of two large surveys,2324 treatment eras were divided into the following three periods: 1988 to 1994 (two-dimensionally planned radiotherapy); 1995 to 1998; and 1999 to 2001 (three-dimensional conformal radiotherapy). Finally, the adjusted effect of radiation therapy on lung cancer survival was evaluated using a Cox proportional hazard regression model after controlling for other cofounders, namely, age at diagnosis, gender, race, and histology.32 The analyses were performed using a statistical software package (SAS; SAS Institute, Cary, NC).


   Results
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
A total of 4,357 patients with unresected stage I or II non-small cell lung cancer were identified. Of those patients, stage I tumors were diagnosed in 3,842 patients (88%) and stage II tumors were diagnosed in 515 patients (12%). The clinicopathologic characteristics of these patients are reported in Table 1 . Patients who received radiation therapy were younger (p = 0.001), more likely to be white (p = 0.01), and more likely to have a squamous cell carcinoma (p = 0.001). The tumor size distribution of patients who underwent radiation therapy and did not undergo radiation therapy was not significantly different (p = 0.12). Approximately 14% of patients treated with radiation had stage II disease compared to 9% of those untreated (p = 0.0001).


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  		Table 1.. Baseline Characteristics of Patients With Unresected Stage I or II Non-small Cell Lung Cancer in SEER, 1988–2001*

 
The lung cancer-specific survival curves of patients with unresected stage I and II tumors who did and did not receive radiation therapy are shown in Figure 1 . Overall, approximately 75% of patients died as a consequence of lung cancer progression. The proportion of patients who died from other causes of death was similar among patients who received radiation therapy and those who did not (stage I patients, 27% vs 23%, respectively; stage II patients, 19% vs 19%, respectively). The lung cancer-specific survival rates of patients who were treated with radiation therapy were statistically significantly better when compared to those of untreated patients (p = 0.0001 and 0.001, respectively) [Table 2 ]. The increment in median survival time, however, was relatively small. The median survival time of patients with stage I tumors who received radiotherapy was 21 months compared to 14 months for patients who had not been treated with radiation therapy. Similarly, the median survival time of patients with stage II lung cancer who received and did not receive radiation therapy was 14 and 9 months, respectively. Thus, the increment in median survival time was 7 months for patients with stage I lung cancer and 5 months for those with stage II lung cancer. The Kaplan-Meier curves suggest that radiation therapy was not curative for these patients since the survival rates of treated and untreated patients were not different approximately 5 years after diagnosis.



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  		Figure 1.. Top: lung cancer-specific survival of unresected stage I tumors according to whether they were treated or not treated with radiation therapy. Bottom: lung cancer-specific survival of unresected stage II tumors according to whether they were treated or not treated with radiation therapy.

 

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  		Table 2.. Lung Cancer Survival Rates for Patients With Unresected Stage I and II Non-small Cell Lung Cancer in SEER*

 
Cox regression models for patients with stage I and II lung cancer showed that all p values for the interaction terms between tumor size and radiation were not significant, suggesting that tumor size did not affect the likelihood of a response to radiation therapy. In separate analyses, the interaction terms for the radiation and treatment period were also not significant, indicating that more recent techniques were not associated with significant improvements in lung cancer survival of patients with unresected tumors.

The unadjusted effect on survival of radiation therapy persisted after controlling for clinicopathologic variables that were known to be associated with lung cancer survival. These analyses showed that radiation therapy was significantly associated with improved lung cancer survival of patients with both stage I and II tumors after adjusting for age, sex, race, and tumor histology (Table 3 ).


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  		Table 3.. Multivariate Cox Regression Analysis for Risk of Lung Cancer Death Among Patients With Unresected Stage I and II Lung Cancer*

 

   Discussion
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
As shown by the SEER, almost 25% of operable non-small cell lung cancers are not resected due to patient refusal or because of coexisting illnesses that preclude surgery. Using a large national database, we found that radiation therapy alone when compared to no treatment is associated with a statistically significant improvement in lung cancer survival of patients with stage I and II lung cancer. The observed increase in median survival time with radiation therapy was only 5 to 7 months. Thus, the long-term outcomes of these patients with stage I and II lung cancer, who have potentially curable disease, is poor. Changes in the current radiation protocols and/or new therapeutic strategies are necessary to improve the outcome of patients with unresected lung cancer.

Several uncontrolled studies491019 have reported improved survival rates or better local control for patients in whom smaller tumors have been diagnosed, concluding that tumor size influences the response to radiation therapy. However, lung cancer tumors diagnosed at a smaller size should demonstrate survival benefit simply based on lead time from earlier diagnosis regardless of the response to treatment.33 To overcome this limitation, we used the Cox regression model to test the effect of tumor size on radiation effectiveness. Using interaction terms between size and radiation, we evaluated whether the effectiveness of radiation varied according to tumor size category (ie, statistically significant interaction terms). None of the interaction terms were significant, suggesting that smaller tumors compared to larger tumors are not likely to be more amenable to cure with radiation therapy.

Two systematic reviews2122 have summarized the outcomes of patients with stage I or II non-small cell lung cancer who were treated with radiation therapy alone because of poor surgical risk or patient refusal of surgery. These studies showed that the 5-year lung cancer survival rate of patients with stage I lung cancer who had been treated with radiation alone was poor, ranging from 13 to 39%. While some studies71117 have suggested better survival rates with increasing doses of radiation, others4818 have not. Some studies have shown that histologic type19 and initial response to radiation9 were associated with improved patient survival. Few studies, however, performed a multivariate analysis to assess the prognostic validity of these factors after adjusting for other potential confounders. None of the studies included an untreated control group. Thus, it is not possible to determine the potential effect of radiation on survival from their findings.

Several strengths and limitations regarding our study should be noted. An advantage of using the SEER registry is that it contains population-based data and, therefore, is less affected by referral patterns and other sources of bias that might be associated with hospital-based case series. Levels of ascertainment within participating areas have been reported to be as high as 98%, showing that most eligible cases are captured in the registry. Additionally, the large number of patients with unresected stage I and II lung cancer in the SEER database allows for the precise estimation of survival rates with and without radiation therapy.

Because this was a retrospective study, the assignment of patients to radiotherapy or no treatment was not random. While we attempted to control for recognized confounding variables, unbalances may have persisted. Physician concerns about potential radiation toxicity could have resulted in a higher prevalence of coexistent illnesses among untreated patients. The observed increased survival with radiation therapy, however, is unlikely to be due to possible comorbidities among the untreated patients. We used lung cancer-specific survival as the outcome for the analyses; thus, possible comorbidities would merely accentuate the frequency of censoring in the Kaplan-Meier analysis. Additionally, the effect of radiation therapy was observed after adjusting for a lack of balance between untreated and treated cases for several factors known to affect lung cancer survival such as age, sex, race, and tumor histology. Whenever a rational indication for an intervention exists, however, it tends to constitute a confounder for the study of its intended effect. The indication, as applied in actual practice, can be quite complex and subtle, and may not be subject to quantification in a nonexperimental design. Thus, unmeasured confounders may explain part of the observed association between radiation therapy and lung cancer survival. Despite this limitation, it is unlikely that a randomized controlled trial comparing radiation therapy vs placebo for patients with unresected stage I or II lung cancer will be conducted in the near future. Thus, in the absence of information from a randomized controlled trial, data from a large, population-based cohort study is probably the best source for evaluating the effectiveness of radiation therapy for these patients.

We found no difference in the outcomes of patients treated across three different treatment periods. However, no data regarding the total radiation dose, fractionation schedule, and radiotherapy technique used to treat each patient is provided in the SEER database. Some patients treated in the latter periods may not have received three-dimensional conformal radiotherapy, which is a technique only recently introduced in some centers in the United States. Thus, it is possible that conformal radiotherapy may achieve better outcomes than those observed in the study, particularly for patients with tumors < 10 mm in diameter. Additionally, we may have underestimated the effect of radiation on lung cancer survival because some of the patients could have received radiation doses of < 60 to 65 Gy. The Radiotherapy Patterns of Care study24 showed, however, that full-dose radiation therapy was the standard of care in most US centers, particularly in the late 1990s. The 1-year, 3-year, and 5-year survival rates for patients who were treated with radiation therapy in our study are well within the range of those reported in prior studies using curative doses, suggesting that most patients in the SEER database were treated according to the standard of care (Table 4 ).41115161718253435 In addition, information regarding radiation therapy provided by SEER has been shown to be approximately 90% accurate.3637


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  		Table 4.. Survival Rates for Patients With Stage I and II Non-small Cell Lung Cancer Treated With Radiation Therapy Alone in SEER and Published Studies*

 
Information regarding the cause of death for patients in the SEER registry was abstracted from death certificates. Although death certificates are an important source of data on disease incidence, disease prevalence, and mortality, inaccuracies in the reported cause of death in this document have been described.3839 For lung cancer patients, however, the underlying cause of death was found to be > 90% accurate in a large registry.40 In addition, estimates of lung cancer survival rates using the SEER registry are similar to those reported in other studies using hospital-based case series.28

Patients with unresected tumors are not pathologically staged, and some patients who were classified as having clinical stage I or II cancer may actually have more extensive disease. One would expect the outcomes for these patients to be worse compared to those for patients with stage I or II cancer who have undergone resection. Our results are clinically relevant nonetheless, given that physicians have only clinical data available when confronted with the decision to offer radiation therapy to patients who will not undergo surgery.

In summary, our study suggests that radiotherapy alone is associated with the improved survival of patients with stage I or II non-small cell lung cancer. The observed increment in median survival time was 5 to 7 months, and radiotherapy did not appear to offer the possibility of cure.


   Footnotes
 
Abbreviations: SEER = Surveillance, Epidemiology, and End Results

Received for publication August 16, 2004. Accepted for publication February 3, 2005.


   References
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 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

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