Abstract
Objective:
As stereotactic body radiation therapy (SBRT) becomes widely available for early-stage non-small cell lung cancer (NSCLC), there may be concerns in the surgical community that SBRT is being offered for patients with operable tumors, even though surgery is standard of care. We evaluated the trends in SBRT and surgery over time for patients with NSCLC.
Methods:
The National Cancer Database was queried for patients with node-negative NSCLC ≤5 cm from 2004–2016. The relationships between definitive local treatment modalities and year were analyzed using a multinomial regression model while controlling for other covariates.
Results:
Among the 202,367 patients who met the inclusion criteria, there was a steady decrease in mean tumor size in all treatment modalities, from 2.44 cm (SD 1.08) to 2.25 cm (SD 1.00) over the study period. In the multinomial model, the probability of receiving lobectomy demonstrated a slight decline from 58% (2004) to 53% (2016). The use of SBRT increased from 1% to 20%, while patients receiving no therapy declined from 27% to 16%. The likelihood of SBRT increased with year of diagnosis (p<0.0001) and decreasing tumor size (p<0.0001), compared to lobectomy. Age, race, income, facility, and Charlson-Deyo score were also associated with treatment modality.
Conclusions:
The mean tumor size of early-stage NSCLC decreased over the study period for all treatment modalities. SBRT use has increased, mostly among older patients with smaller tumors and Charlson-Deyo scores ≥3. The increase in SBRT contributed to the significant decline in patients who had no therapy.
Keywords: NSCLC, SBRT, lobectomy, thoracic surgery, patient selection
Introduction
Curative intent treatment for early-stage primary non-small cell lung cancer (NSCLC) traditionally consists of anatomic pulmonary resection with mediastinal lymphadenectomy.1–3 Over the past decade, stereotactic body radiation therapy (SBRT), or stereotactic ablative radiotherapy (SABR), has emerged as a popular treatment modality for both primary as well as secondary lung malignancies. SBRT takes advantage of advanced treatment planning and tumor localization techniques to deliver focused, high, ablative dose to the tumor without the perioperative risks of invasive procedures.4,5
While lobectomy results in significant decline in lung function, SBRT often results in small decreases in pulmonary function measurements that do not significantly affect patients’ performance status or symptoms,6 with similar DLCO changes as sublobar resections.7 Therefore, early applications of SBRT for primary NSCLC focused on individuals deemed medically unfit for surgical resection. Outcomes in this population have been encouraging, with several studies demonstrating durable, long-term disease-free survival with limited treatment-related morbidity.8–11 Several retrospective and non-randomized trials have been performed attempting to compare surgery and SBRT indirectly.4,7,12–17 To date, the only randomized data comparing lobectomy and SBRT in medically operable patients is a pooled analysis of two trials (STARS and ROSEL) that closed early due to slow accrual.18 While the pooled analysis supports the use of SBRT for operable early-stage NSCLC, the small sample size and short follow-up warrant further investigation.19 In the subsequent revised STARS trial, which compared a larger SBRT cohort to a propensity-matched surgical group, long-term survival after SBRT was non-inferior to surgery.20
Ongoing trials, such as VALOR (NCT02984761), attempt to establish the optimal treatment modality for operable patients. In the meantime, despite a paucity of level one evidence, SBRT has had an expanding role in the treatment of primary NSCLC in recent decades. This may generate concerns in the surgical community that patients who would benefit from surgery, which is still standard of care, could be inappropriately offered SBRT.21–23 In this study, we investigate treatment patterns for early-stage NSCLC in the United States’ National Cancer Database (NCDB), with a focus on patient selection for SBRT. We hypothesize that the increase in SBRT reflects the increased treatment of patients who might not have been surgical candidates (e.g., small tumors, elderly, or co-morbidities). Previous national database studies involving similar topics used older datasets when SBRT was still in its infancy, and included conventional radiation schedules that do not represent the modern treatment paradigm.24,25
Materials and Methods
Data Source
The participant user file (PUF) of NCDB, sourced from hospital registry data at Commission on Cancer (CoC)-accredited facilities, was utilized for the completion of this study. Data represent more than 70% of newly diagnosed cancer in the United States. The NCDB is a joint project of the CoC of the American College of Surgeons and the American Cancer Society. The data used in the study are derived from a de-identified NCDB file. The American College of Surgeons and the CoC have not verified and are not responsible for the analytic or statistical methodology employed, or the conclusions drawn from these data by investigators. The patients’ informed consent for publication of study data was waived by IRB due to the nature of the study.
Cohort Selection
The NCDB PUF was queried for patients with clinical T1-T3 and ≤5 cm, N0 NSCLC from Jan. 1, 2004 to Dec. 31, 2016 (Fig. S1). Since the focus of this study was on the patterns of treatment over time and tumor size, it was decided to exclude T3 disease greater than 5 cm. The size was chosen based on what is commonly treated with SBRT.8,26,27 Tumors greater than 5 cm are also more often associated with other treatment modalities, such as use of post-operative chemotherapy, neoadjuvant chemoradiation, and use of more extensive surgery. Carcinoid histology, neoadjuvant chemotherapy or radiation therapy, and patients less than 18 years of age were excluded. Patients were divided into groups based on the primary treatment received: (1) lobectomy, (2) sublobar resection, (3) SBRT, and (4) no treatment. Other types of surgeries, including pneumonectomies, were excluded, as such cases would be atypical for NSCLC ≤5cm and would not be classified as early-stage. Sublobar resection included anatomic segmentectomy as well as wedge resections. The SBRT group was defined as treatment fraction of ≤5, with total dose of at least 30 Gy, based on commonly used dose and fractionation schedules (34 Gy in 1, 45–54 Gy in 3, 48–50 Gy in 4, 50–60 Gy in 5, etc.).11,26,28,29 Using these criteria, 96.3% of patients received a biologic effective dose (BED) greater than or equal to 100 Gy (α/β=10Gy). For the purpose of the study, we focused on SBRT use and excluded conventional or hypofractionated radiation schedules, which are less favored compared to SBRT due to longer treatment times and less data on efficacy.30–32 Similarly, percutaneous ablation was also not included.33,34
Variable Selection and Statistical Analysis
The primary outcome analyzed was modality of therapy. The year of diagnosis was used as a categorical variable, with 2004 as reference group. Patient-specific variables included age, gender, race, insurance type, median household income, education level, area of residence, tumor size, facility type, Charlson-Deyo Score, and histology group. Age at diagnosis was recategorized into 4 groups: <=50, 50–60, 60–70, >70 years. Race included white, black, and other. Median household income of the patient’s ZIP code was dichotomized at above or below $63,000 based on availability from the NCDB. Education level was dichotomized based on more or fewer than 7% of the adults in the patient’s ZIP Code who were without a high school degree. Primary insurance was categorized as Medicare/Medicaid, private, other, and uninsured. Area of residence included metropolitan, urban, and rural. Facility type included community cancer center, comprehensive cancer center, academic center, and other. Tumor size was analyzed as a categorical variable in 1 cm increments due to its non-linear relationship with the logit. Tumor histology group was defined using International Classification of Diseases for Oncology (ICD-O) codes for NSCLC, including: adenocarcinoma, squamous cell, and other.
Descriptive analyses were reported with frequency and percentages. Multinomial logistic regression was used to evaluate the association between independent variables and treatment groups using relative risk ratios (RRRs) using cases with no missing variables, resulting in exclusion of 9% of patients who were included in the descriptive analyses Variables were excluded from final model if p>0.05. In addition, those with documented contraindications to surgery or radiation were excluded from the multinomial analysis. Predicted probabilities for treatment group across year of diagnosis was generated using the final model. Multinomial assumption of independence of irrelevant alternatives (IIA) was tested by Hausman test.35 Both SBRT and no treatment groups held IIA assumption. Lobectomy and sublobar resection showed non-independence. However, the likelihood-ratio test suggested that it would be inappropriate to combine the categories. Therefore, we kept the four categories for analyses. Due to the large sample size, a p-value of <0.001 was considered statistically significant in the multivariable analysis.36,37 All analyses were performed using SAS version 9.4 (SAS Institute Inc., Cary, North Carolina).
Results
From 2004 to 2016, there were 202,367 patients who met study criteria (Supplementary Figure S1, Supplemental Digital Content 1, http://links.lww.com/AJCO/A410). Approximately half of the patients (N=100,694, 49.8%) underwent lobectomy over the course of the entire study period. The mean age was 70.6 ± 9.6 years (median 71, range 18–90), with slightly more females (53.3%) than males. Detailed patient and clinical characteristics are shown in Table 1. As summarized in Figure 1, the total number of N0 NSCLC up to 5 cm contained in the NCDB increased from 2004 (5,348) to 2016 (24,406), with a large increase in total number of patients in 2008 related to TNM staging becoming mandatory in the NCDB. This allowed for more patients to be captured by the inclusion criteria for the current study. SBRT had the largest magnitude of increase over the study period (80 in 2004 to 7,951 in 2016), followed by lobectomy (3,081 to 10,279), sublobar resection (1,113 to 3,764), and no treatment (1,074 to 2,412), (Supplementary Table S1, Supplemental Digital Content 1, http://links.lww.com/AJCO/A410). The mean size of treated tumors for all modalities decreased over the study period from 2.44 ± 1.08 (mean ± SD) to 2.22 ± 1.00 cm (with overall median 2.10, range 0.1–5.0). When broken down by treatment group, a similar trend was seen across all modalities of therapy (Figure 2, p<0.0001 for each group). On the other hand, a near-linear increase in average age of the patients were observed from 2004 (70.1) to 2016 (70.9). When examining the average age by each treatment modality, the age remained relatively stable over time (Supplementary Figure S2, Supplemental Digital Content 1, http://links.lww.com/AJCO/A410). After adjusting for age, tumor size, race, insurance, income, education, facility, comorbidity scores, and location, the probability of receiving a specific modality of therapy using marginal means by year is shown in Figure 3. The probability of receiving lobectomy slightly declined from 58% in 2004 to 53% in 2016. The use of SBRT increased from 1% to 20%, while patients receiving no therapy declined from 27% to 16% over the study period. As compared to lobectomy, the likelihood of receiving SBRT increased each year (p<0.0001). Tumor sizes >2 cm was associated with a decreased likelihood of receiving SBRT compared to lobectomy (p<0.0001). Confidence intervals and the effects of other covariates are shown in Table 2. Patients who were recorded to have contraindications for surgery or radiation were excluded for the purpose of Table 2. However, when the same analysis was run for the entire 202,367 patients, there was no difference in the trend or significance level between the variables and treatment modalities.
Table 1.
Patient and disease characteristics of early-stage NSCLC treated in the U.S. from 2004 to 2016
| Sublobar Resection N=35764 | Lobectomy N=100694 | No Therapy N=23439 | SBRT N=42470 | |||||
|---|---|---|---|---|---|---|---|---|
| Mean | Std | Mean | Std | Mean | Std | Mean | Std | |
|
| ||||||||
| Tumor size (mm) | 18.2 | 8.5 | 23.8 | 10.2 | 26.9 | 11.4 | 22.7 | 9.5 |
| Age | 70.3 | 9.2 | 68.4 | 9.3 | 74.1 | 9.8 | 74.2 | 8.8 |
|
| ||||||||
| N | (%) | N | (%) | N | (%) | N | (%) | |
|
| ||||||||
| Age | ||||||||
| <= 50 yr. | 881 | (2.46) | 3889 | (3.86) | 360 | (1.57) | 233 | (0.55) |
| 50–60 | 4337 | (12.13) | 16312 | (16.2) | 1935 | (8.43) | 2934 | (6.91) |
| 60–70 | 11793 | (32.97) | 35818 | (35.57) | 5246 | (22.87) | 10545 | (24.85) |
| >70 | 18753 | (52.44) | 44675 | (44.37) | 15402 | (67.13) | 28721 | (67.69) |
|
| ||||||||
| Gender | ||||||||
| Male | 15654 | (43.77) | 46123 | (45.81) | 11285 | (49.19) | 19756 | (46.56) |
| Female | 20110 | (56.23) | 54571 | (54.19) | 11658 | (50.81) | 22677 | (53.44) |
|
| ||||||||
| Race | ||||||||
| White | 32171 | (89.95) | 89394 | (88.78) | 19405 | (84.58) | 37953 | (89.44) |
| Black | 2543 | (7.11) | 7748 | (7.69) | 2747 | (11.97) | 3507 | (8.26) |
| Other | 814 | (2.28) | 2959 | (2.94) | 626 | (2.73) | 665 | (1.57) |
| Missing | 236 | (0.66) | 593 | (0.59) | 165 | (0.72) | 308 | (0.73) |
|
| ||||||||
| Charlson-Deyo Score | ||||||||
| 0 | 16011 | (44.77) | 50202 | (49.86) | 12159 | (53) | 23390 | (55.12) |
| 1 | 12755 | (35.66) | 34341 | (34.1) | 6113 | (26.64) | 11130 | (26.23) |
| 2 | 4986 | (13.94) | 11754 | (11.67) | 2955 | (12.88) | 5196 | (12.25) |
| >=3 | 2012 | (5.63) | 4397 | (4.37) | 1716 | (7.48) | 2717 | (6.4) |
|
| ||||||||
| Education* | ||||||||
| <7% | 9025 | (25.23) | 23265 | (23.1) | 4175 | (18.2) | 9582 | (22.58) |
| >7% | 26593 | (74.36) | 77015 | (76.48) | 18661 | (81.34) | 32775 | (77.24) |
| Missing | 146 | (0.41) | 414 | (0.41) | 107 | (0.47) | 76 | (0.18) |
|
| ||||||||
| Median Income | ||||||||
| <63,000 | 22877 | (63.97) | 69039 | (68.56) | 17176 | (74.86) | 30434 | (71.72) |
| >63,000 | 12727 | (35.59) | 31193 | (30.98) | 5650 | (24.63) | 11907 | (28.06) |
| Missing | 160 | (0.45) | 462 | (0.46) | 117 | (0.51) | 92 | (0.22) |
|
| ||||||||
| Facility | ||||||||
| Academic | 14084 | (39.38) | 34626 | (34.39) | 5914 | (25.78) | 17285 | (40.73) |
| Community Cancer Center | 2441 | (6.83) | 6625 | (6.58) | 2818 | (12.28) | 1618 | (3.81) |
| Comprehensive Cancer Center | 14589 | (40.79) | 44655 | (44.35) | 11029 | (48.07) | 16507 | (38.9) |
| Other | 4566 | (12.77) | 14521 | (14.42) | 3165 | (13.8) | 7019 | (16.54) |
| Missing | 84 | (0.23) | 267 | (0.27) | 17 | (0.07) | 4 | (0.01) |
|
| ||||||||
| Insurance | ||||||||
| Insured | 7909 | (22.11) | 27795 | (27.6) | 3188 | (13.9) | 5349 | (12.61) |
| Medicare/Medicaid | 26808 | (74.96) | 69286 | (68.81) | 18707 | (81.54) | 34777 | (81.96) |
| Other | 312 | (0.87) | 991 | (0.98) | 323 | (1.41) | 1520 | (3.58) |
| Uninsured | 353 | (0.99) | 1512 | (1.5) | 407 | (1.77) | 290 | (0.68) |
| Missing | 382 | (1.07) | 1110 | (1.1) | 318 | (1.39) | 497 | (1.17) |
|
| ||||||||
| Histology | ||||||||
| Adenocarcinoma | 24047 | (67.24) | 68420 | (67.95) | 11303 | (49.27) | 20686 | (48.75) |
| Squamous | 10354 | (28.95) | 28700 | (28.5) | 8015 | (34.93) | 15100 | (35.59) |
| Other | 1363 | (3.81) | 3574 | (3.55) | 3625 | (15.8) | 6647 | (15.66) |
Based on percentage of adult residents in patients’ ZIP Code at time of diagnosis who did not graduate from high school. <7% represents patients who lived in a better educated area.
Figure 1. Definitive local therapy for early stage NSCLC in the U.S. from 2004 to 2016.
During the study period, the number of patients steadily increased across all treatment modalities, with the largest absolute increase in the SBRT group (80 in 2004 to 7,951 in 2016), and the smallest in the No Treatment group (1,074 to 2,412). *In 2008, TNM staging was mandated, resulting in an increase in patient capture rate. Also see accompanying Supplemental Table S1, Supplemental Digital Content 1, http://links.lww.com/AJCO/A410.
Figure 2. Mean tumor size (mm) by treatment modality.
Error bars represent the 95% confidence interval. From 2004 to 2016, the average tumor size decreased steadily across all treatment modalities for node negative, early-stage non-small cell lung cancer up to 5 cm contained in the NCDB.
Figure 3. Probability of treatment modality predicted by multinomial logistic regression model.
Accounting for analyzable confounding variables, the likelihood of a patient receiving SBRT for node-negative non-small cell lung cancer up to 5 cm has increased dramatically from 2004 to 2016. On the other hand, the likelihood of patient receiving no definitive local therapy has nearly halved, while the probability of patients undergoing surgery has also decreased slightly over the same period. See accompanying Table 2.
Table 2.
Multivariable analysis of management of early-stage NSCLC treated in the U.S. from 2004 to 2016
| SBRT vs Lobectomy | Sublobar Resection vs Lobectomy | No Treatment vs Lobectomy | |
|---|---|---|---|
|
| |||
| RRR (95% CI) | RRR (95% CI) | RRR (95% CI) | |
|
| |||
| Year of Diagnosis | |||
| 2004 | Reference | Reference | Reference |
| 2005 | 1.404 (1.02–1.94) | 1.01 (0.91–1.12) | 0.93 (0.83–1.05) |
| 2006 | 3.36 (2.53–4.46)a | 0.97 (0.88–1.07) | 0.91 (0.81–1.01) |
| 2007 | 6.11 (4.67–7.98)a | 0.98 (0.89–1.08) | 0.78 (0.69–0.87)a |
| 2008 | 5.60 (4.31–7.28)a | 0.88 (0.81–0.97) | 0.58 (0.52–0.64)a |
| 2009 | 7.45 (5.75–9.65)a | 0.87 (0.80–0.95) | 0.54 (0.49–0.60)a |
| 2010 | 10.09 (7.80–13.05)a | 0.89 (0.82–0.97) | 0.60 (0.55–0.67)a |
| 2011 | 12.53 (9.69–16.20)a | 0.93 (0.85–1.01) | 0.59 (0.53–0.65)a |
| 2012 | 15.61 (12.09–20.17)a | 0.95 (0.87–1.04) | 0.65 (0.59–0.71)a |
| 2013 | 17.77 (13.76–22.94)a | 0.95 (0.87–1.03) | 0.68 (0.62–0.75)a |
| 2014 | 19.86 (15.38–25.64)a | 0.99 (0.91–1.07) | 0.74 (0.67–0.82)a |
| 2015 | 23.55 (18.25–30.39)a | 0.98 (0.90–1.06) | 0.73 (0.67–0.81)a |
| 2016 | 25.29 (19.60–32.64)a | 0.94 (0.87–1.03) | 0.67 (0.61–0.74)a |
|
| |||
| Tumor Size | |||
| 0–1 cm | Reference | Reference | Reference |
| 1–2 cm | 0.99 (0.94–1.05) | 0.49 (0.47–0.51)a | 0.78 (0.73–0.84)a |
| 2–3 cm | 0.83 (0.79–0.88)a | 0.25 (0.24–0.26)a | 0.87 (0.81–0.93)a |
| 3–4 cm | 0.69 (0.64–0.73)a | 0.15 (0.14–0.16)a | 1.12 (1.04–1.21) |
| 4–5 cm | 0.53 (0.49–0.57)a | 0.10 (0.09–0.11)a | 1.62 (1.50–1.76)a |
|
| |||
| Age | |||
| ≤50 | Reference | Reference | Reference |
| 50–60 | 2.81 (2.35–3.35)a | 1.21 (1.11–1.33)a | 1.29 (1.13–1.48)b |
| 60–70 | 4.10 (3.45–4.87)a | 1.47 (1.35–1.60)a | 1.46 (1.28–1.66)a |
| >70 | 9.41 (7.91–11.12)a | 2.04 (1.87–2.23)a | 3.13 (2.75–3.56)a |
|
| |||
| Race | |||
| White | Reference | Reference | Reference |
| Black | 1.10 (1.04–1.16)b | 0.98 (0.93–1.03) | 1.90 (1.80–2.01)a |
| Other | 0.52 (0.46–0.55)a | 0.78 (0.72–0.85)a | 1.16 (1.05–1.28) |
|
| |||
| Insurance | |||
| Medicare/Medicaid | Reference | Reference | Reference |
| Private | 0.62 (0.60–0.65)a | 0.83 (0.80–0.86)a | 0.69 (0.66–0.66)a |
| Uninsured | 0.73 (0.62–0.85)a | 0.88 (0.78–1.00) | 1.66 (1.46–1.88)a |
| Other | 3.42 (3.10–3.78)a | 0.92 (0.80–1.05) | 1.66 (1.44–1.92)a |
| Unknown | 1.11 (0.98–1.26) | 0.93 (0.82–1.05) | 1.25 (1.08–1.44) |
|
| |||
| Median Household Income | |||
| <63,000 | Reference | Reference | Reference |
| ≥63,000 | 0.78 (0.75–0.81)a | 1.19 (1.15–1.23)a | 0.82 (0.78–0.86)a |
|
| |||
| Education* | |||
| <7% | Reference | Reference | Reference |
| ≥7% | 0.99 (0.95–1.03) | 1.05 (1.01–1.09) | 1.18 (1.12–1.24)a |
|
| |||
| Facility | |||
| Academic center | Reference | Reference | Reference |
| Community cancer center | 0.48 (0.44–0.51)a | 0.98 (0.93–1.04) | 2.44 (2.30–2.59)a |
| Comprehensive cancer center | 0.70 (0.67–0.72)a | 0.82 (0.79–0.84)a | 1.43 (1.37–1.49)a |
| Other | 0.95 (0.91–0.99) | 0.78 (0.75–0.82)a | 1.27 (1.20–1.34)a |
|
| |||
| Charlson-Deyo score | |||
| 0 | Reference | Reference | Reference |
| 1 | 0.67 (0.65–0.70)a | 1.18 (1.15–1.21)a | 0.66 (0.64–0.69)a |
| 2 | 0.79 (0.75–0.82)a | 1.36 (1.31–1.42)a | 0.83 (0.79–0.88)a |
| ≥3 | 0.99 (0.93–1.06) | 1.51 (1.42–1.60)a | 1.19 (1.11–1.28)a |
|
| |||
| Location | |||
| Metropolitan | Reference | Reference | Reference |
| Urban | 1.32 (1.10–1.59) | 0.83 (0.67–1.02) | 0.77 (0.60–1.00) |
| Rural | 1.20 (0.48–3.01) | 1.17 (0.48–2.87) | 1.69 (0.61–4.67) |
Based on percentage of adult residents in patients’ ZIP code at time of diagnosis who did not graduate from high school. <7% represents patients who lived in a better educated area.
p<0.0001
p<0.001
RRR: relative risk ratio.
To better understand patient selection for SBRT, we explored why surgery was not done in these patients. In the SBRT group, 70% (n=29,806) of the patients did not get surgery because an alternate treatment was recommended as first-line therapy, and approximately 24% (n=10,260) of the patients were specifically recorded to have contraindications to surgery due to risk factors, while 5% (n=2,271) of the patients refused surgery. There was no notable change across the study period in these reasons for not receiving surgery. The reasons documented for why SBRT patients did not receive surgery are provided by the year in Table 3 and Supplementary Figure S3. Unfortunately, further details, such as the specific conditions that prohibited surgery, were not available in the NCDB beyond what is reported, Supplemental Digital Content 1, http://links.lww.com/AJCO/A410.
Table 3.
Reasons documented for SBRT patients not getting surgery by year
| Not offered as first line treatment | Died prior to treatment | Contraindicated due to risk factors | No reason | Refused | Unknown if performed | Total/year | |
|---|---|---|---|---|---|---|---|
|
| |||||||
| 2004 | 57 | 3 | 4 | 5 | 6 | 75 | |
| 2005 | 91 | 27 | 3 | 11 | 132 | ||
| 2006 | 249 | 134 | 2 | 26 | 411 | ||
| 2007 | 572 | 244 | 8 | 46 | 870 | ||
| 2008 | 938 | 411 | 6 | 64 | 1419 | ||
| 2009 | 1467 | 572 | 11 | 131 | 2181 | ||
| 2010 | 2066 | 750 | 7 | 159 | 5 | 2987 | |
| 2011 | 2514 | 856 | 4 | 178 | 3 | 3555 | |
| 2012 | 3083 | 1060 | 4 | 251 | 8 | 4406 | |
| 2013 | 3704 | 1302 | 5 | 279 | 3 | 5293 | |
| 2014 | 4157 | 1495 | 8 | 312 | 4 | 5976 | |
| 2015 | 5152 | 1626 | 9 | 411 | 4 | 7202 | |
| 2016 | 5756 | 2 | 1780 | 12 | 398 | 3 | 7951 |
|
| |||||||
| Total | 29806 | 2 | 10260 | 83 | 2271 | 36 | 42458 |
| % | 70.20% | 0.00% | 24.17% | 0.20% | 5.35% | 0.08% | |
Discussion
Our results show that the adoption of SBRT as curative intent therapy for primary NSCLC steadily increased over the course of the study period. In the early 2000’s, SBRT was considered a new and experimental technology. The first phase I study by Timmerman et al. had not been published until 2003, and it was not until 2004, that large multi-institutional outcome from Japan was made available by Onishi et al.29,38 Therefore, it is not surprising to see few patients receiving SBRT in 2004, with increases every subsequent year. A previous study by Corso et al. similarly showed increased use of SBRT from 2004–2011.39 Our results describe what has happened in the more recent years, especially considering seminal publications from the Indiana University SBRT study and RTOG 0236 were published in 2009 and 2010, respectively.8,40
Although there may be concerns from thoracic surgeons and radiation oncologist that patients eligible for surgical resection are inappropriately being offered SBRT, our adjusted analyses suggest that the rise in SBRT use has been in older patients, patients with smaller tumors, and patients with Charlson-Deyo comorbidity score ≥3. Similar studies have come from the Netherlands, where the increase in SBRT use in the elderly was associated with a decrease in the percentage of untreated patients.41,42 While we did not focus on patient outcome, previous studies, including the aforementioned studies from the Netherlands, have demonstrated clear improvement in survival and other metrics in patients who receive SBRT compared to no definitive local treatment.21,41–43 With increased awareness and adoption of new technology by more centers and physicians, the use of SBRT is likely to continue to increase over time.
In the later years of the current study, there is a slight decline in the use of surgery as definitive treatment (Figure 3). As surgery and SBRT are such different treatment modalities with different morbidity and mortality risk, the decreased percentage of surgeries may raise concern that patient preference could be driving the increased use of SBRT in medically operable patients. While that would be hard to disprove, the reasons for not receiving surgery have remained largely unchanged over the study period (Supplementary Figure S3, Supplemental Digital Content 1, http://links.lww.com/AJCO/A410). However, there are many limitations in how reasons for treatment selection are coded in NCDB, such as the inability to obtain the specific conditions that prohibited patients from getting surgery or account for multifactorial motives.
The data shows that therapy options correlated with the Charlson-Deyo comorbidity scores. Charlson-Deyo scores ≥3 (worse comorbidities) was associated with increased likelihood of patients getting any therapy other than lobectomy (Table 2). However, this trend did not hold for Charlson-Deyo scores of 1 or 2 for SBRT and no treatment. In other words, patients receiving a lobectomy were more likely to have comorbidity scores of 1 or 2 compared to 0 than patients in the SBRT or “no treatment” groups. Without adjusting for covariates, the percentage of patients with comorbidity scores of 0 were slightly higher in the SBRT (55%) and “no treatment” (53%) groups than in the lobectomy group (50%). These results are contrary to expectations that patients without comorbidities should be getting surgery. This raises an important limitation in using the Charlson-Deyo score for NCDB analysis. In NCDB, patients are assumed to have scores of 0 if no diagnosis codes are submitted. There is no way to differentiate if there are truly no documented comorbidities or if comorbidity information was unavailable.44 The NCDB has previously been shown to underestimate CD score in NSCLC patients, particularly for conditions such as congestive heart failure, and chronic pulmonary disease.44,45 There is also concern for less rigorous documentation of comorbidities in non-surgical patients. Those who undergo surgery are evaluated by the surgeon, along with PFTs and other pre-operative work up, increasing the chance of specific comorbidities being documented in their records. On the other hand, those deemed appropriate for SBRT and no definitive therapy may lack such detailed formal workup and therefore are less likely to have their comorbidities clearly documented. While we cannot definitively say that these reasons explain our findings, we highlight the limitations of assessing comorbidities using NCDB data. Knowing the specific comorbidities that would alter treatment recommendation for NSCLC, such as interstitial lung disease or chronic obstructive pulmonary disease (COPD) would have been helpful in better understanding patient selection. Unfortunately, individual non-cancer diagnosis codes and PFTs are not available in the NCDB. However, the prevalence and severity of these comorbidities are expected to stay relatively steady among the entire population over the study period but increase with increasing age. Therefore, controlling for the patient age in statistical analyses can help indirectly accounts for such confounding factors.
As the number of cases included in the study increased over the years, a steady decrease in tumor size was noted, also seen within each of the treatment groups (Fig. 2). The finding likely reflects improved imaging quality and frequency, as well as increased screening for high-risk patients, leading to the detection of smaller lesions.46 The data also showed that while the average age of each treatment modality group remained steady to slightly down-trending over time, the average age of the overall sample steadily increased over the study period, reflecting an aging population in the United States. We hypothesize that the rise in SBRT use comes largely from treatment of patient who would otherwise receive no treatment at all, such as in older patients with incidentally detected small tumors. Again, this data is in line with data from the Netherlands.41,42 While the proportion of patients getting surgery did decline over time (Supplementary Table S1, Supplemental Digital Content 1, http://links.lww.com/AJCO/A410), the difference became smaller after controlling for various variables with multinomial regression (Figure 3). For example, lobectomy decreased from 58% in the 2004 cohort to 42% in 2016, but after accounting for other variables, the likelihood change was 58% to 53%. On the other hand, those getting no therapy decreased from 27 to 16%, while SBRT increased from 1 to 20%. While the advancement of SBRT technology likely drew patients from all groups over the course of the study, it appears to have contributed particularly in providing definitive local therapy to those who would not have received surgery.
While the lesion size decreased overall, the statistically significant larger lesion size in the no treatment group is hypothesis-generating. While a portion of these patients may have been medically unfit for any therapy, and others could have received non-standard therapy (i.e. systemic therapy only, percutaneous ablation) not captured by the NCDB, it is still concerning that so many patients did not undergo some form of definitive local therapy, either surgery or SBRT. With the wide adoption of minimally invasive surgical techniques such as robot-assisted and video-assisted thoracic surgery, as well as improvement in SBRT and other hypofractionated high-dose radiation techniques, it is possible that more patients with larger tumors may safely progress through definitive local therapy in the future.47,48
The choice to pursue a given therapy is often a complex decision attempting to balance short-term risk with long-term benefit. Both access to, and the risk of, SBRT and surgery vary by location and can add an additional layer of complexity to the decision tree. Our regression analysis suggested that not only were patient and lesion specific characteristics predictive of the receipt of a specific modality of therapy (size and age), but the center type also predicted the modality of therapy administered. Patients treated at academic centers were more likely to receive any treatment versus no treatment, and if treated, had a higher likelihood of receiving SBRT (Table 2). However, the rate of no treatment has been decreasing in the more recent years at community centers, with trend of increase in SBRT use, highlighting the effort to acquire advanced radiation technology and adoption of effective treatment for early stage NSCLC at such centers.49 The availability of technology could have contributed to the changes in treatment modality percentage. For example, a borderline resectable patient in 2004 at a community center may have gone to surgery, whereas the same patient in 2016 might have chosen SBRT as an alternative.
As with any large database study, there are inherent limitations to the current study. While every attempt was made to control for confounders using multinomial analysis, it is still not possible to control for the effects of all factors fully. In addition, there were issues that could not be accounted for. Due to the lack of disease-specific survival data, it was not possible to confirm whether the change of treatment patterns during the study period resulted in improvement in lung cancer-related mortality. The accuracy and consistency of coding in the database is also a concern, as patients with the wrong diagnosis and stage could have been included. Similarly, variability in methods used for staging could have affected the accuracy, especially for nodal staging. The majority of patients had no specific reason for not undergoing surgery, which, along with the lack of more detailed patient comorbidities (including performance status, PFTs, pack-year smoking history, specific existing medical issues etc.) limit the ability to analyze the appropriateness of treatment selection. In addition, since we excluded certain treatment modalities and tumors >5 cm, there may be limited external validity in applying our findings to all early-stage NSCLC patients in the United States. Finally, with mean and median age of the study population over 70, the predetermined categories of age used in the analysis are biased towards a younger population.
Conclusion
While lobectomy remains the most common, and preferred, treatment, there has been a significant increase in the rate of SBRT use from 2004 to 2016, with a corresponding decrease in patients getting no treatment. The size of tumor decreased across all treatment modalities, likely reflecting early detection of small disease. Those receiving no local treatment (surgery or SBRT) tended to have the largest tumors. Further studies are necessary in identifying additional barriers causing patients to not receive therapy for a disease with high cure rates. Every patient with early-stage NSCLC should be evaluated for surgery by a multidisciplinary team including a thoracic surgeon, with SBRT being offered as an alternative treatment in patients unfit for or unwilling to undergo resection.
Supplementary Material
Acknowledgements
This work was supported by grants UL1TR001855 and UL1TR000130 from the National Center for Advancing Translational Science (NCATS) of the U.S. National Institutes of Health. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
Source of Funding:
This work was supported by grants UL1TR001855 and UL1TR000130 from the National Center for Advancing Translational Science (NCATS) of the U.S. National Institutes of Health.
Abbreviations:
- CoC
Commission on Cancer
- NCDB
National Cancer Database
- NSCLC
Non-small cell lung cancer
- PFT
Pulmonary function test
- PUF
Participant user file
- RRR
Relative risk ratio
- SABR
Stereotactic ablative radiotherapy
- SBRT
Stereotactic body radiation therapy
- SD
Standard deviation
Footnotes
Conflicts of Interest
The authors do not have any conflict of interest to disclose.
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