Stereotactic body radiation therapy versus no treatment for early stage non–small cell lung cancer in medically inoperable elderly patients: A National Cancer Data Base analysis
The data used in this study are derived from a deidentified National Cancer Data Base file. The National Cancer Data Base is a joint project of the Commission on Cancer of the American College of Surgeons and the American Cancer Society. The American College of Surgeons and the Commission on Cancer have not verified and are not responsible for the analytic or statistical methodology used, or the conclusions drawn from these data by the investigator.
Stereotactic body radiation therapy (SBRT) has demonstrated high rates of local control with low morbidity and has now emerged as the standard of care for medically inoperable, early stage non–small cell lung cancer (NSCLC). However, the impact of lung SBRT on survival in the elderly population is less clear given competing comorbid conditions. An analysis of the National Cancer Data Base (NCDB) was undertaken to determine whether definitive SBRT improves survival relative to observation alone patients ages 70 years and older.
The NCDB, a retrospective national database that captures approximately 70% of all patients treated for cancer, was queried for patients aged 70 years or older with early stage (T1-T3N0M0) NSCLC from 2003 to 2006. Overall survival was compared between patients who received stereotactic body radiotherapy alone and those who received no treatment. An extended Cox proportional hazards model was applied to estimate the treatment effect of SBRT.
In total, 3147 patients met the selection criteria for this analysis. SBRT was delivered to 258 patients (8.2%), and 2889 patients (91.8%) received no treatment. There was no significant difference in the distribution of Charlson/Deyo comorbidity index scores between the 2 groups (P = .076). Multivariable analysis revealed improved overall survival with SBRT compared with observation for the entire cohort (hazard ratio, 0.64; P < .001).
SBRT is associated with improved survival in elderly patients with early stage NSCLC who have concurrent comorbid conditions compared with observation alone. The current data support the use of SBRT for the treatment of elderly patients with early stage NSCLC who have limiting comorbid conditions. Cancer 2015;121:4222–4230. © 2015 American Cancer Society.
Approximately 20% of patients diagnosed with non–small cell lung cancer (NSCLC) present with localized, technically resectable, early stage disease, for which surgical resection with lobectomy and lymph node sampling remain the standard of care in medically fit patients.1 However, elderly patients with early stage NSCLC often have significant competing conditions, including chronic obstructive lung disease, coronary artery disease, dementia, and other smoking and nonsmoking-related diseases. Consequently, surgical resection of early stage disease is often not possible secondary to concerns of surgery-related morbidity and mortality. Definitive radiation therapy with conventional fractionation (1.8-2.0 grays [Gy] daily) yields poor long-term outcomes, with survival rates ranging from 20% to 30%.2-4 However, an improvement in disease control with radiation compared with observation is reported5; and, without treatment, nearly 50% of patients die rapidly from progressive disease.6 Over the last decade, the use of lung stereotactic body radiation therapy (SBRT) has increased dramatically.7 From a technical point of view, SBRT is characterized by the delivery of high-dose radiation in 1 to 5 fractions with a high degree of precision and steep dose gradients that minimize the dose to normal tissues. In patients with medically inoperable lung cancer, SBRT has produced dramatically improved outcomes relative to conventional fractionated radiation, with local control rates >90%, comparable to the rates achieved with lobectomy8, 9 or sublobar resection.10 Furthermore, SBRT is associated with low volumes of normal tissues receiving irradiation and sharp dose gradients and, thus, is well tolerated with low rates of toxicity.11
To date, no head-to-head, prospective comparisons between SBRT and surgery in medically operable patients have been completed because of poor accrual, but available retrospective data suggest the possibility that the 2 may yield comparable local control and survival outcomes, especially when analyses are controlled for comorbidity and age.12-14 A recently completed pooled analysis of those randomized trials indicates that SBRT may be equivalent to surgery in medically operable patients.15 Nonetheless, surgery remains the standard of care in this population. Conversely, in the medically inoperable population, SBRT is accepted as the standard of care for early stage disease. However, whether the excellent local control rates11 translate into an overall survival benefit is less clear, especially in the elderly population, in which a potentially limited life expectancy may not allow for a long-term survival benefit from treatment. Several retrospective studies indicate poor survival with no treatment, but the numbers are limited, and those data have not been analyzed in the era of SBRT.6, 16 Multiple factors may contribute to the reasons why elderly patients do not receive definitive treatment for early stage disease. Although it has been demonstrated that SBRT offers excellent local control with low morbidity,17 it is unclear whether SBRT improves survival in elderly patients who are limited by concomitant medical conditions. Given the lack of prospective data available to answer this question, the objective of the current study was to evaluate the impact on survival of definitive radiation therapy with SBRT compared with no treatment in elderly patients with early stage NSCLC using the NSCLC National Cancer Data Base (NCDB).
MATERIALS AND METHODS
The NCDB is a large database that is prospectively acquired and maintained by the American College of Surgeons’ Commission on Cancer and the American Cancer Society. The database draws on information gathered from Commission on Cancer-accredited cancer centers nationwide and currently captures 70% of all diagnosed malignancies in the United States annually. The data set includes detailed information on patient characteristics, disease parameters, treatment information, and outcomes. The treatment information contains data not available in other large national databases, including detailed radiotherapy information regarding treatment site, treatment source, radiation dose (in Gy), and treatment technique as well as information regarding the receipt of chemotherapy. Emory University was granted access to the NCDB NSCLC database, which contains 1,547,531 patients who were diagnosed between 1998 and 2011.
The primary objective of this study was to estimate the difference in overall survival, measured from the date of diagnosis to the date of either death or last follow-up, between patients who received SBRT and those who received no treatment for primary NSCLC. Patients aged 70 years and older with American Joint Committee on Cancer T1 through T3 tumors,18 lymph node-negative (N0), nonmetastatic (M0), primary NSCLC who received either lung SBRT or no treatment were included in this analysis. Only patients who were diagnosed between 2003 and 2006 were included, because comorbidity information was not reported before 2003, and 5-year survival information on patients who received treatment after 2006 was not yet available. Patients who received conventional radiation therapy were excluded. Patients who had 1 lifetime cancer or for whom the reported tumor was the first of multiple diagnoses were included to avoid confounding effects from treatments for a prior cancer diagnosis. Patients who were diagnosed at the reporting facility but received treatment elsewhere were excluded (Fig. 1). Patient demographics and disease characteristics included age (in groups ages 70-74 years, 75-79 years, 80-84 years, and 85 years and older), Charlson/Devo comorbidity index score, year of diagnosis, sex, race, type of treatment facility, insurance status, income (median household income in the patient's zip code of residence), education level (percentile without high school graduation in the patient's zip code of residence), urban versus rural residence, histology, pathologic grade, clinical T-classification, and tumor size (in millimeters).
Statistical analyses were conducted using SAS version 9.3 (IBM Corporation, Armonk, NY) and SAS macros developed by the Biostatistics and Bioinformatics Shared Resource at Winship Cancer Institute (Atlanta, Ga).19 Descriptive statistics were reported for each variable. The univariate association with treatment group (SBRT vs no treatment) was assessed using chi-square tests for categorical covariates and analyses of variance for numeric covariates. Overall survival was measured in months from the date of diagnosis to the date of either death or last follow-up. To account for the leading survival time in patients who received SBRT, an extended Cox model was used to estimate treatment effects by setting treatment as a time-dependent variable. The extended Cox model allows for the possibility that, although membership in the classifying treatment group may change dynamically over time, the model maintains full statistical power and also controls for guarantee-time bias.20, 21 A multivariable Cox model was fit using a backward variable selection method to select the covariates, applying an α value of .20 for removal criteria, in which treatment was set as a time-dependent variable. In addition, interaction models were fit to test the treatment effect across age groups or Charlson/Deyo scores. An extended Kaplan-Meier estimator22 was plotted to compare treatment for all patients and by age group.
The NSCLC NCDB identified 3147 patients who were diagnosed between 2003 and 2006, received either SBRT or no treatment and, and were eligible for the current analysis. Figure 1 illustrates the patient selection and exclusion criteria. Complete patient and treatment characteristics are provided in Table 1. The majority of patients in the analysis received no treatment (n = 2889), and 258 patients received SBRT. Patients who were not surgical candidates but received conventional radiation rather than SBRT were excluded (n = 3591) from the analysis. The median age of the entire cohort was 79 years, and the median follow-up was 78.5 months. The majority of patients were coded with American Joint Committee on Cancer stage I NSCLC (90%), and nearly all (97.5%) had histologically confirmed cancer of the primary site.
|No. of Patients (%)|
|Covariate||No Treatment, N = 2889||SBRT N = 258||Parametric Pa|
|Community cancer program/other||534 (18.48)||5 (1.94)||<.001b|
|Comprehensive community cancer program||1776 (61.47)||130 (50.39)|
|Academic/research program (includes NCI)||579 (20.04)||123 (47.67)|
|Men||1408 (48.74)||112 (43.41)||.101|
|Women||1481 (51.26)||146 (56.59)|
|70-74||715 (24.75)||75 (29.07)||.108|
|75-79||872 (30.18)||87 (33.72)|
|80-84||745 (25.79)||56 (21.71)|
|≥85||557 (19.28)||40 (15.5)|
|No||363 (12.69)||13 (5.1)||< .001b|
|Yes||2497 (87.31)||242 (94.9)|
|Not insured||14 (0.5)||0 (0)||.366|
|Private insurance||278 (9.85)||30 (11.67)|
|Government insurance||2530 (89.65)||227 (88.33)|
|<$30,000||539 (19.35)||42 (17.87)||< .001b|
|$30,000-34,999||589 (21.15)||26 (11.06)|
|$35,000-45,999||798 (28.65)||65 (27.66)|
|≥$46,000||859 (30.84)||102 (43.4)|
|≥29%||625 (22.44)||35 (14.89)||.002b|
|20%-28.9%||717 (25.75)||52 (22.13)|
|14%-19.9%||656 (23.55)||58 (24.68)|
|<14%||787 (28.26)||90 (38.3)|
|Metropolitan area||2217 (80.41)||184 (80)||.879|
|Urban/rural||540 (19.59)||46 (20)|
|0||1701 (58.88)||170 (65.89)||.076|
|1||781 (27.03)||55 (21.32)|
|≥2||407 (14.09)||33 (12.79)|
|Year of diagnosis|
|2003||901 (31.19)||15 (5.81)||< .001b|
|2004||717 (24.82)||29 (11.24)|
|2005||677 (23.43)||72 (27.91)|
|2006||594 (20.56)||142 (55.04)|
|Other||177 (6.13)||5 (1.94)||.009b|
|NSCLC NOS||758 (26.24)||82 (31.78)|
|Squamous cell carcinoma||979 (33.89)||77 (29.84)|
|Adenocarcinoma||975 (33.75)||94 (36.43)|
|1-2||673 (23.3)||50 (19.38)||.005b|
|3-4||763 (26.41)||51 (19.77)|
|Unknown, high-grade dysplasia||1453 (50.29)||157 (60.85)|
|AJCC clinical T classification|
|T1||1286 (44.51)||170 (65.89)||< .001b|
|T2||1315 (45.52)||83 (32.17)|
|T3||288 (9.97)||5 (1.94)|
|NCDB analytic stage group|
|Stage I||2581 (89.34)||252 (97.67)||< .001b|
|Stage II||308 (10.66)||6 (2.33)|
|Mean tumor size, cm||3.78||2.8||< .001b|
- Abbreviations: AJCC, American Joint Committee on Cancer; NCDB, National Cancer Data Base; NCI, National Cancer Institute; NOS, not otherwise specified; NSCLC, non–small cell lung cancer.
- a Parametric P values were calculated using an analysis of variance for numerical covariates and chi-square tests for categorical covariates.
- b These P values indicate a statistically significant difference.
The median time from diagnosis to the receipt of definitive radiation in the SBRT group was 2.3 months. A mean of 3.89 fractions (median, 3 fractions) to a mean dose of 5397 centigrays (cGy) (median, 5325 cGy) was delivered to patients in the SBRT group. There was greater use of SBRT in academic/research programs (47.7%) and comprehensive community cancer programs (50.4%) than in community cancer programs (1.9%; P < .001). Patients from zip codes that represented a higher median household income also were more likely to receive SBRT. The rates of SBRT increased with each successive year from 2003 to 2006 (P < .001). There was no statistically significant difference between patients who received SBRT and those who did not based on Charlson/Deyo comorbidity index scores (no treatment: 90.9%, 93.4%, and 92.5%; SBRT: 9.1%, 6.6%, and 7.5%, for scores of 0, 1, and ≥2, respectively; P = .076). Additional details regarding differences in treatment according to demographics and tumor characteristics are noted in Table 1.
Univariate survival analyses indicated improved survival with SBRT over observation (Supporting Table 1; see online supporting information). Men, older patients, and patients who received treatment in earlier years had worse survival than their counterparts. Conversely, patients with smaller tumors and earlier T-classification had better survival.
Multivariable survival analysis according to the main effects of treatment (Table 2) confirmed an improvement in survival with SBRT over observation (hazard ratio [HR], 0.64; P < .001). For the entire cohort of patients, the median overall survival was 29 months with SBRT versus 10.1 months with observation alone (P < .001) (Fig. 2). Survival was better for women (HR, 0.86; P < .001), nonwhite patients (HR, 0.86; P = .043), patients with low comorbidity indices (Charlson/Deyo score, 0-1; P < .001), patients with adenocarcinoma (P < .001), and those with earlier T-classification (P < .001). The multivariable survival analysis with interaction between treatment and age groups or Charlson/Deyo comorbidity index scores enabled us to estimate the treatment effect within each strata defined by age or comorbidity score (Table 3). Survival was significantly improved with SBRT for all age groups (ages 70-74 years: HR, 0.72 [P = .028]; ages 75-79 years: HR, 0.66 [P = .004]; ages 80-84 years: HR, 0.59 [P = .003]; and ages 85 years and older: HR, 0.56 [P = .006]) (Fig. 3A-D). The survival benefit with SBRT also was significant, regardless of the number of comorbidities (Charlson/Deyo score of 0: HR, 0.64 [P < .001]; Charlson-Deyo score ≥2: HR, 0.51 [P = .002]).
|Covariateb||HR (95% CI)||HR||Type 3|
|Year of diagnosis|
|AJCC clinical tumor classification|
|Tumor size, cm||1.06 (1.05-1.07)||<.001a||<.001c|
|Comparison: SBRT vs no treatmentd|
- Abbreviations: AJCC, American Joint Committee on Cancer; CI, confidence interval; HR, hazard ratio; SBRT, stereotactic body radiation therapy.
- a Of the total observations (n = 3147) in the original data set, 2278 observations were used.
- b The variables facility type, insurance, grade, and urban/rural were excluded.
- c These P values indicate a statistically significant difference.
- d The HR for SBRT is from a comparison between SBRT and no treatment, with SBRT treated as a time-varying variable.
|Strata||Treatment||HR (95% CI)||HR P|
|70-74||SBRT vs observation||0.72 (0.53-0.97)||.028a|
|75-79||SBRT vs observation||0.66 (0.49-0.88)||.004a|
|80-84||SBRT vs observation||0.59 (0.42-0.83)||.003a|
|≥85||SBRT vs observation||0.56 (0.37-0.85)||.006a|
|0||SBRT vs observation||0.64 (0.52-0.78)||<.001a|
|1||SBRT vs observation||0.79 (0.56-1.11)||.173|
|≥2||SBRT vs observation||0.51 (0.33-0.77)||.002a|
- Abbreviations: CI, confidence interval; HR, hazard ratio. SBRT, stereotactic body radiation therapy.
- a These P values indicate a statistically significant difference.
Although lobectomy is the standard of care for medically fit patients with early stage NSCLC, elderly patients and those with poor pulmonary function or multiple comorbidities often are not candidates for surgery. SBRT is the standard of care for medically inoperable patients, but it is unclear whether the excellent local control rates achieved with SBRT11 translate into a survival benefit. Emerging data suggest that, even for patients who are medically operable with resectable disease, SBRT may be at least equivalent to surgery in terms of local control and survival outcomes.15 However, patients with multiple medical comorbidities may forego definitive treatment, because they may not perceive a meaningful benefit to treatment given their advanced age and multiple comorbid conditions, which may be perceived as more immediately life-threatening than early stage NSCLC.
Small series and meta-analyses have demonstrated that the median overall survival of patients with untreated, early stage NSCLC ranges from 5 to 14 months.2, 6, 16 Lung cancer-specific survival reportedly was poor for untreated patients with early stage disease compared with treated patients (5-year cancer-specific survival, 23% for untreated T1 tumors vs 72% for treated T1 tumors).23 The majority of those patients died from progressive cancer resulting in distant metastases or respiratory compromise rather than comorbid conditions.6 There is also evidence that elderly patients may not require extensive treatment, and sublobar resection yielded survival comparable to that achieved with lobectomy in some series.24 Shirvani et al12 reported on Surveillance, Epidemiology, and End Results data comparing lobectomy, sublobar resection, conventional radiation, SBRT, and observation in patients older than age 65 years. SBRT and lobectomy were associated with the lowest risk of death, whereas conventional radiation and observation were associated with poor overall survival and lung cancer-specific survival. A national database from the Netherlands further demonstrated that the introduction of SBRT was associated with an increase in the use of radiation therapy in elderly patients, a decline in the proportion of untreated patients, and an improvement in overall survival.7 However, those data need to be validated in the US population, given the differences in smoking rates (which are higher in the Netherlands for both men and women)25 and the systematic differences in health care coverage, expenditure, and access to care26 as well as inherent differences in patient populations within and between countries.
Our analysis of the NCDB illustrates that, in patients aged 70 years and older, there is a clear overall survival benefit from treatment with SBRT as opposed to observation alone. The relative risk of death was reduced by 36% with SBRT in this population, and the benefit was maintained across all age groups, even beyond age 85 years. These results corroborate findings from the Netherlands, which also indicated high control rates in inoperable elderly patients with early stage lung cancer who received SBRT.27 A strong trend, likely limited by the sample size of the population, toward improved survival (Table 2) with each successive year of treatment from 2003 to 2006 suggests improved SBRT techniques (although this effect may be secondary to lead-time bias alone), translating into reduced acute and late radiation toxicities, which can have an impact on overall survival. For example, high rates of clinically significant toxicity were observed in patients who received high-dose SBRT to the central bronchial tree in the early SBRT studies,11 but those toxicity rates were not immediately apparent during the early stages of adopting SBRT. It should be noted these findings are hypotheses-generating, because information regarding toxicity and the quality of radiation delivery is not available in the NCDB. Regardless, greater experience with this technology presumably will translate into a greater benefit-risk ratio for elderly patients with early stage NSCLC. The current data indicate that patients in the highest median household income group were more likely to receive SBRT and also demonstrate a compelling trend toward improved survival (P = .058), which, again, probably fell short of statistical significance because the analysis was underpowered. Although a causal relation cannot be drawn, this information does underscore the need to offer and to ensure access to SBRT for all patients, including making referrals to centers capable of high-quality SBRT if needed, to provide the best care and offer the best chance of survival. It may be argued that the survival benefit observed in this population is attributable to a treatment effect alone rather than SBRT itself; however, a recent study using the National Lung Cancer Data Base comparing SBRT with conventionally fractionated radiation demonstrated a benefit from SBRT in that setting as well.28
There has been a trend in recent years toward greater consideration of the risk-benefit ratio of certain treatments for elderly patients or those with limited life expectancy who are diagnosed with early stage cancers. The rationale is to limit unnecessary treatment and associated side effects in patients who may not derive a meaningful benefit from definitive treatment in terms of either cure or control. For example, results from Cancer and Leukemia Group B study 9343 indicate that, for a select group of women older than 70 years with early stage breast cancer, adjuvant radiation therapy may safely be eliminated after lumpectomy if they receive endocrine therapy for 5 years.29 Similarly, active surveillance or observation is recommended by the National Comprehensive Cancer Network for men with low-risk prostate cancer and a limited life expectancy.30 In these groups, the possibility that a patient may die from some other cause, rather than from the cancer itself, is taken into consideration. The question is often raised whether the same rationale can be applied to patients with early stage NSCLC. This question is becoming more and more relevant with the adoption of lung cancer screening programs and improved resolution of computed tomography scanners, which may result in the diagnosis of more patients at early stages, either because of screening or as an incidental finding. Although lung cancer screening is only recommended for patients who are able and willing to undergo curative lung surgery, often, the determination of surgical fitness is made only after the diagnosis of cancer. Our current study indicates that, even in patients who have multiple comorbid conditions, as indicated by a higher Charlson/Deyo comorbidity index score, a survival benefit with SBRT is observed, suggesting that the main driver of mortality in this population is lung cancer.
Use of the NCDB in the current analysis confers several benefits over other databases, including a large sample size, the availability of radiation therapy details (including dose, fractionation, treatment technique, and source), and treatment site. Data also could be broken down by specific age group, thereby demonstrating that even the most elderly patients—for whom there is most often contention regarding whether or not to treat—derive a benefit from SBRT. However, the NCDB is limited by its inherent retrospective nature, the potential for miscoding, and its incremental 5-year survival data. Miscoding may have led to the relatively small sample size of patients who received SBRT in this study, and many patients simply may not be represented by these data. Consequently, the treatment population in this study was small, and any conclusions from these data must be tempered by the small sample size. Furthermore, the database lacks data regarding toxicity and quality of life. However, SBRT is generally well tolerated, with extremely low rates of clinically significant adverse effects,31, 32 even within the elderly population.17, 27 There were also relatively small numbers of patients who received SBRT compared with observation, likely because SBRT was in the early stages of adoption during the period of this study. In addition, it is unclear how these results can be extrapolated to minorities and patients who have larger tumors, because these groups were relatively underrepresented in the current study. Finally, the reasons why patients or providers opt for observation over definitive treatment, aside from perceived futility, cannot be elucidated. For example, the inability of patients to travel to SBRT-equipped facilities (although patients who received treatment at a facility different from that of diagnosis were excluded) or to lie flat for 30 to 60 minutes, which is required for SBRT treatment, or reluctance by providers to treat larger lesions may contribute toward patients receiving no treatment and may be important factors in clinical and patient decision making but cannot be determined from the NCDB. Conversely, some patients who received SBRT, particularly those with low comorbidity scores, may have been surgical candidates but declined resection, leading to superior survival in this cohort. However, there was no significant difference in comorbidity scores between patients who did and did not receive SBRT, which makes this a less likely confounder.
The current results support the treatment of elderly, medically inoperable patients who have early stage NSCLC, including those who have multiple comorbidities, with definitive SBRT. A significant improvement in survival is noted in patients who receive SBRT until at least age 85 years relative to observation alone. SBRT should be considered as part of patient and provider decision making for elderly, medically inoperable patients who have early stage NSCLC.
The research reported in this publication was supported in part by the Biostatistics and Bioinformatics Shared Resource of Winship Cancer Institute of Emory University and by the National Institutes of Health/National Cancer Institute under award P30CA138292. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
CONFLICT OF INTEREST DISCLOSURES
The authors made no disclosures.
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