Nonoperative Treatment of Large (5–7 cm), Node-Negative Non–Small Cell Lung Cancer Commonly Deviates From NCCN Guidelines

Authors: Craig S. Schneider MD, PhD1, Robert A. Oster PhD2, Aparna Hegde MBBS3, Michael C. Dobelbower MD, PhD1, John M. Stahl MD1, and Adam J. Kole MD, PhD1
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  • 1 Department of Radiation Oncology,
  • | 2 Division of Preventative Medicine, Department of Medicine, and
  • | 3 Division of Hematology and Oncology, Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama.

Background: Optimal treatment of nonoperative patients with large, node-negative non–small cell lung cancer (NSCLC) is poorly defined. Current NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) recommend definitive radiotherapy (RT) with or without sequential chemotherapy and do not include concurrent chemoradiotherapy (chemoRT) as a treatment option. In this study, we identified factors that predict nonadherence to NCCN Guidelines. Patients and Methods: Patients who received definitive RT for nonmetastatic, node-negative NSCLC with tumor size of 5 to 7 cm were identified in the National Cancer Database from 2004 through 2016. Patients were evaluated by RT type (stereotactic body RT [SBRT], hypofractionated RT [HFRT], or conventionally fractionated RT [CFRT]) and chemotherapy use (none, sequential, or concurrent with RT). Patients were classified as receiving NCCN-adherent (RT with or without sequential chemotherapy) or NCCN-nonadherent (concurrent chemoRT) treatment. Demographic and clinical factors were assessed with logistic regression modeling. Overall survival was evaluated with Kaplan-Meier, log-rank, and univariable/multivariable Cox proportional hazards regression analyses. Results: Among 2,020 patients in our cohort, 32% received NCCN-nonadherent concurrent chemoRT, whereas others received NCCN-adherent RT alone (51%) or sequential RT and chemotherapy (17%). CFRT was most widely used (64% CFRT vs 22% SBRT vs 14% HFRT). Multivariable analysis revealed multiple factors to be associated with NCCN-nonadherent chemoRT: age ≤70 versus >70 years (odds ratio [OR] , 2.72; P<.001), treatment at a nonacademic facility (OR, 1.65; P<.001), and tumor size 6 to 7 cm versus 5 to 6 cm (OR, 1.27; P=.026). Survival was similar between the NCCN-nonadherent chemoRT and NCCN-adherent groups (hazard ratio, 1.00; P=.992) in multivariable analysis. Conclusions: A substantial proportion of inoperable patients with large, node-negative NSCLC are not treated according to NCCN Guidelines and receive concurrent chemoRT. Younger patients with larger tumors receiving treatment at nonacademic medical centers were more likely to receive NCCN-nonadherent therapy, but adherence to NCCN Guidelines was not associated with differences in overall survival.

Background

Surgical therapy is the mainstay of treatment of early-stage non–small cell lung cancer (NSCLC), particularly in the node-negative setting. For medically inoperable patients with node-negative disease, curative therapy typically involves definitive radiotherapy (RT). Although stereotactic body RT (SBRT) alone has become a standard therapy for small inoperable tumors, the optimal treatment of patients with larger (5–7 cm) tumors is less clear.

The role of chemotherapy for early-stage NSCLC is best defined in the postoperative setting and is frequently used for tumors >4 cm or when other high-risk features are present.16 For patients with inoperable node-negative disease receiving definitive RT, however, prospective data evaluating the role of chemotherapy are lacking. As a result, based on extrapolations of surgical data, NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for NSCLC recommend the consideration of chemotherapy for high-risk patients with inoperable disease.7 In addition to the uncertainties surrounding chemotherapy use, data are also lacking regarding ablative SBRT techniques for larger tumors, given that patients with tumors >5 cm were generally excluded from major prospective SBRT trials.812

In this study, we sought to analyze practice patterns for patients with large (5–7 cm), node-negative NSCLC with regard to chemotherapy use and RT technique. Given the lack of prospective data defining optimal treatment, we hypothesized that treatment paradigms would commonly stray from NCCN Guidelines and sought to identify factors associated with receipt of NCCN-nonadherent therapy. The impact of treatment paradigm on overall survival (OS) was also evaluated.

Patients and Methods

Study Population

We identified patients in the National Cancer Database (NCDB) diagnosed from 2004 to 2016 with histologically confirmed, clinically node-negative NSCLC measuring between 5.0 and 7.0 cm. All patients had AJCC 6th or 7th edition clinical stage cT2N0M0 disease; thus, patients with more extensive disease (eg, chest wall invasion, separate tumor nodules) were excluded. Patients with the following histologies were included: adenocarcinoma, squamous cell carcinoma, NSCLC not otherwise specified (NOS), large cell carcinoma, and adenosquamous carcinoma (ICD-O-3 codes 8012–8014, 8046, 8070–8076, 8078, 8140, 8141, 8143, 8147, 8250–8255, 8560, 8562).

We excluded patients with a prior cancer diagnosis, those receiving surgery to the primary site, those who did not receive external-beam RT, those with unknown RT fraction number or dose, and those with unknown chemotherapy status.

For the purposes of this study, RT was classified into the following types: conventionally fractionated RT (CFRT), defined as 60 to 70 Gy in 30 to 38 fractions using ≤2 Gy/fraction; SBRT, defined as 48 to 60 Gy in ≤5 fractions; and hypofractionated RT (HFRT), defined as 50 to 72 Gy in >5 fractions using >2 Gy/fraction.13 Patients not meeting these RT criteria were excluded from the study, including those receiving palliative doses of ≤30 Gy or receiving nonstandard escalated RT doses of >72 Gy. Patients with an unusual dose per fraction (defined as a specific dose per fraction with <10 patients receiving it) were also excluded.

For patients receiving chemotherapy, chemotherapy was classified as either concurrent (defined as ≤7 days between initiation of chemotherapy and RT) or sequential (defined as >7 days between initiation of chemotherapy and RT). Treatment was classified as NCCN-adherent if patients received RT alone or sequential RT with chemotherapy as per NCCN Guidelines (Version 3.2020).7 Treatment was considered NCCN-nonadherent if the patient received concurrent chemoRT.

A summary of the patient population with inclusion and exclusion criteria is provided in supplemental eFigure 1 (available with this article at JNCCN.org).

Statistical Methods

Demographic and clinicopathologic factors extracted from the NCDB were analyzed via chi-square testing to examine their effect on receipt of NCCN-adherent versus NCCN-nonadherent therapy. Factors assessed included age, sex, race/ethnicity, Charlson-Deyo (CD) score, insurance coverage, treatment facility, and tumor size. Factors were dichotomized for univariable and multivariable logistic regression analyses to assess association with receipt of NCCN-adherent versus NCCN-nonadherent therapy. Age was dichotomized at a cutoff of 70 years, given the older overall age distribution of our cohort. Tumor size was dichotomized at midpoint size of our cohort inclusion criteria (5–7 cm): <6 versus ≥6 cm. Year of diagnosis was similarly dichotomized into 2 even groups: 2004 through 2010 versus 2011 through 2016. CD score was dichotomized as 0 to 1 versus ≥2. Univariable Cox regression was performed to compute unadjusted odds ratios (ORs) for receipt of NCCN-adherent versus NCCN-nonadherent therapy. Factors trending toward statistical significance (as defined by P<.10 in univariable analysis) were included in multivariable logistic regression to determine adjusted ORs. A value of P<.05 was considered statistically significant. Trends in RT and chemotherapy use over time were determined via Spearman rank correlation coefficient (for continuous time data) and chi-square testing (for dichotomized time data, 2004–2010 vs 2011–2016).

OS was evaluated with Kaplan-Meier analyses, log-rank tests, and univariable and multivariable Cox proportional hazards regression analyses with dichotomized demographic and clinicopathologic variables. Only factors trending toward significance (as defined by P<.10) in univariable survival analysis were included in multivariable analysis, with P<.05 considered statistically significant. Notably, survival analyses were performed on 1,783 of the original 2,020 patients in the final cohort. Patients were excluded from survival analyses if survival data were not provided by the NCDB (eg, patients diagnosed in 2016 and one additional patient diagnosed in 2012). An additional 18 patients who died within 3 months of diagnosis were excluded to minimize immortal time bias.14

The NCDB is a joint project of the Commission on Cancer (CoC) of the American College of Surgeons and the American Cancer Society. The data used in the study were derived from a deidentified NCDB file. The American College of Surgeons and the CoC have not verified and are not responsible for the analytic or statistical methodology used or the conclusions drawn from these data by the investigators.

Results

Based on inclusion and exclusion criteria, a total of 2,020 patients with 5- to 7-cm node-negative NSCLC were included in the final cohort (supplemental eFigure 1). Median follow-up was 18.7 months. Median age was 75 years, with most patients being male (57.9%), non-Hispanic White (81.8%), and having a CD comorbidity score of 0 to 1 (80.3%). Other demographic factors for the total cohort are presented in Table 1. Tumor size was between 5 and 6 cm for most patients (61.8%), and the remainder of patients had tumor sizes between 6 and 7 cm. Nearly half of the patients (49.3%) received chemotherapy as part of their initial, definitive treatment, with 32.2% receiving concurrent chemoRT and 17.1% receiving sequential RT and chemotherapy. Most patients received CFRT (64.3%), whereas SBRT (21.8%) and HFRT (13.9%) were less common. The most commonly used RT fractionation regimen for each category can be found in supplemental eTable 1.

Table 1.

Patient Characteristics

Table 1.

Figure 1 summarizes the initial treatment of patients with regard to chemotherapy use and RT type. The most common treatment paradigm was concurrent chemoRT using conventional fractionation, with 31% of patients receiving this treatment despite the lack of support by NCCN Guidelines.7 Patients receiving SBRT (22%) and HFRT (14%) only rarely received chemotherapy, with most being treated with definitive RT alone.

Figure 1.
Figure 1.

Patterns of chemotherapy and radiotherapy use.

Abbreviations: CFRT, conventionally fractionated radiotherapy; HFRT, hypofractionated radiotherapy; SBRT, stereotactic body radiotherapy.

Citation: Journal of the National Comprehensive Cancer Network 2021; 10.6004/jnccn.2021.7043

Given the high rate of nonadherence to NCCN Guidelines regarding the use of concurrent chemoRT, we investigated factors associated with receipt of NCCN-nonadherent therapy. Patients receiving concurrent chemoRT were classified as NCCN-nonadherent, whereas all other patients (ie, those receiving definitive RT alone or RT with sequential chemotherapy) were classified as NCCN-adherent. Clinicopathologic and demographic factors of these 2 patient populations are reported in supplemental eTable 2. To determine factors associated with selection of NCCN-nonadherent therapy, univariable and multivariable regressions were performed (Table 2). In univariable analysis, younger age (<70 years), male sex, private insurance, treatment at a nonacademic center, and larger tumor size (≥6.0 cm) were associated with receipt of NCCN-nonadherent therapy. In multivariable analysis, age <70 years (OR, 2.72; P<.001), treatment at a nonacademic center (OR, 1.65; P<.001), and larger tumor size (≥6.0 cm; OR, 1.27; P=.026) remained statistically associated with receipt of NCCN-nonadherent therapy.

Table 2.

Factors Associated With Nonadherence to NCCN Guidelines

Table 2.

We evaluated whether the use of NCCN-nonadherent concurrent chemoRT changed during the study period (Figure 2). There was a statistically similar number of patients receiving NCCN-nonadherent chemoRT from 2004 to 2016 (range, 28%–40%; Spearman ρ = 0.02; P=.415). With regard to RT type, practice patterns changed substantially with increasing use of SBRT (Spearman ρ = 0.18; P<.0001) and, to a lesser extent, HFRT (Spearman ρ = 0.06; P=.098). In particular, SBRT use jumped from the 0% to 10% range in 2004 through 2007 to 25% to 30% by 2013 through 2016. This was accompanied by a corresponding decreased use of conventional fractionation over the same time period. Patient factors associated with the use of SBRT were analyzed with univariable and multivariable logistic regressions (supplemental eTable 3). In univariable analysis, older age (>70 years), non-Hispanic White race, year diagnosed (2011–2016), nonprivate insurance, treatment at an academic center, and smaller tumor size (<6.0 cm) were significantly associated with receipt of SBRT. In subsequent multivariable analysis, age ≥70 years (OR, 1.64; P<.001), non-Hispanic White race (OR, 1.57; P=.011), year of diagnosis 2011 through 2016 (OR, 2.48; P<.001), treatment at an academic center (OR, 3.24; P<.001), and tumor size <6 cm (OR, 2.52; P<.001) were statistically associated with receipt of SBRT.

Figure 2.
Figure 2.

Trends in (A) chemotherapy and (B) radiotherapy use over time in our cohort. A statistically significant trend of increased use of SBRT (Spearman ρ = 0.1775; P<.001) and HFRT was found (Spearman ρ = 0.058; P=.010) with corresponding decreased use of CFRT (Spearman ρ = −0.1955; P<.001). Comparison of (C) chemotherapy and (D) radiotherapy use from 2004 through 2010 and 2011 through 2016.

Abbreviations: CFRT, conventionally fractionated radiotherapy; HFRT, hypofractionated radiotherapy; SBRT, stereotactic body radiotherapy.

* P<.001 by chi-square analysis.

Citation: Journal of the National Comprehensive Cancer Network 2021; 10.6004/jnccn.2021.7043

The effect of treatment pattern on OS was evaluated. Supplemental eFigure 2 illustrates Kaplan-Meier survival curves for patients based on the use of chemotherapy and RT type. In log-rank analysis, patients receiving either sequential or concurrent chemotherapy had prolonged survival compared with those not receiving chemotherapy (P<.001). However, there was no difference between patients receiving sequential chemotherapy and those receiving concurrent chemotherapy (P=.895). Median survival data and log-rank analyses are reported for each treatment group in supplemental eTables 4 and 5. For the entire cohort, median OS was 21 months (95% CI, 19.8–22.1). The longest median OS was observed for patients receiving SBRT with sequential chemotherapy (36 months; 95% CI, 25.7–53.4), although this was not statistically significant compared with all other groups receiving chemotherapy.

To examine factors associated with survival, and in particular to assess the impact of NCCN-adherent versus NCCN-nonadherent therapy, univariable and multivariable regression analyses were performed (Table 3). Although NCCN-adherent versus NCCN-nonadherent therapy was associated with increased risk of mortality in univariable analysis, multivariable analysis failed to show a significant effect when controlling for other factors (hazard ratio [HR], 1.00; 95% CI, 0.85–1.18; P=.992). Factors that were associated with increased risk of mortality included older age (≥70 vs <70 years; HR, 1.17; 95% CI, 1.04–1.33; P=.011), male versus female sex (HR, 1.28; 95% CI, 1.15–1.43; P<.001), CD score ≥2 versus 0 to 1 (HR, 1.25; 95% CI, 1.09–1.43; P=.001), diagnosis year 2004 through 2010 versus 2011 through 2016 (HR, 1.15; 95% CI, 1.03–1.28; P=.014), nonprivate insurance versus private insurance (HR, 1.27; 95% CI, 1.08–1.49; P=.004), tumor size ≥6.0 versus <6.0 cm (HR, 1.21; 95% CI, 1.09–1.35; P=.001), and no chemotherapy versus chemotherapy (HR, 1.27; 95% CI, 1.09–1.49; P=.002).

Table 3.

Factors Associated With Mortality

Table 3.

Discussion

The optimal treatment of patients with inoperable, large, node-negative NSCLC remains unclear. NCCN Guidelines7 recommend definitive RT with or without adjuvant chemotherapy for these patients, based mostly on extrapolations from similarly staged surgical patients, in whom adjuvant chemotherapy improves outcomes for patients with high-risk features (eg, tumors >4 cm).1 6 Concurrent chemoRT is not currently recommended by NCCN Guidelines,7 because key trials defining the role of definitive chemoRT in locally advanced NSCLC generally excluded node-negative patients.15 19

In this study, we found that roughly one-third of patients with NSCLC with 5- to 7-cm primary tumors received concurrent chemoRT, which is not supported by NCCN Guidelines.7 Other treatment strategies, including SBRT, HFRT, or CFRT with or without sequential chemotherapy, were used less often than NCCN-nonadherent chemoRT. Multivariable analysis suggests that clinicians elected the concurrent chemoRT treatment strategy for younger (presumably more fit) patients with larger tumors. Interestingly, the use of concurrent chemoRT remained stable over the entire time period studied (2004–2016), suggesting that this is an engrained practice among some physicians, regardless of current national guidelines.

Although the use of concurrent chemoRT in node-negative patients is not backed by high-level data, the frequent use of this approach is not necessarily surprising. It is known that patients with larger primary tumors are at high risk for regional nodal and distant failure.20 , 21 Specifically among patients with primary tumors ≥5 cm, retrospective SBRT series have shown distant failure to be the most common mode of failure, with 31% to 33% of all patients developing distant metastases.22 24 Data from several prospective studies have similarly shown high rates of distant failure for node-negative NSCLC, with RTOG 0236 reporting a distant failure rate of 45% at 5 years for patients with T2 tumors8 and RTOG 0917 reporting rates of any distant failure to be 44% to 47%.10 In locally advanced NSCLC, concurrent chemoRT is known to be superior in terms of locoregional control and OS compared with sequential RT in several randomized controlled trials and meta-analyses.15 17 , 25 Although increased esophageal toxicity is expected among node-positive patients receiving RT to the mediastinum, there may be a lower perceived risk of toxicity in our study cohort of node-negative patients, in whom lower RT doses to the esophagus are expected.

We did not observe an association between OS and adherence to NCCN Guidelines when adjusting for other factors in multivariable analysis. Although a survival benefit with receipt of NCCN-nonadherent therapy was seen in univariable analysis, this was likely a result of the confounding variable of chemotherapy, which by definition was administered to all patients receiving NCCN-nonadherent concurrent chemoRT. In contrast, only 25% of patients in the NCCN-nonadherent group received chemotherapy. In multivariable survival analysis, lack of receipt of chemotherapy was associated with worse OS. Although this could partially be attributed to selection bias (with fitter patients receiving chemotherapy), studies in similar cohorts of patients receiving definitive RT have consistently shown an OS benefit with the addition of chemotherapy13 , 26 , 27 to definitive RT. Despite this, only half of our cohort received chemotherapy, likely due to comorbidities and poor functional status that are common in patients with NSCLC (eg, older age, smoking history, chronic obstructive pulmonary disease). For patients unable to tolerate traditional chemotherapy, immunotherapy is an emerging potential systemic treatment option that may reduce distant failure and improve outcomes in this population,28 with several trials underway investigating SBRT + immunotherapy in patients with T1–3N0M0 NSCLC (eg, ClinicalTrials.gov identifiers: NCT03110978 and NCT03833154). Although the NCDB did begin to include an immunotherapy variable starting in 2013, this variable does not include standard immunotherapy agents used in NSCLC (eg, durvalumab and other PD-1/PD-L1 inhibitors); thus, it remains unknown whether patients in our cohort received immunotherapy .

The classification of SBRT in this study was based on US billing standards, in which SBRT is defined as ≤5 fractions. However, other more protracted regimens with high biologically effective doses (BEDs; BED at α/β ratio of 10 [BED10], >100) are often also considered SBRT. For example, 2 regimens (7 Gy × 10 fractions = 70 Gy and 7.5 Gy × 8 fractions = 60 Gy) were used in 33 patients in our study, who were included in our HFRT cohort. We performed a sensitivity analysis using a more inclusive SBRT definition (BED10, >100) and found that the major results and conclusions of this study were unchanged, regardless of classification of these patients (data not shown). Similarly, for the classification of chemotherapy as sequential or concurrent, we performed a sensitivity analysis assessing the effect of defining concurrent chemotherapy as 3 days, 10 days, or 14 days within the initiation of RT. No substantial changes in our main conclusions were seen (data not shown).

This study has several limitations. First, as previously mentioned, given the retrospective nature of this study, there is inherent selection bias that may have influenced treatment selection and therefore survival analyses. Although multivariable analyses were performed to try to account for some of these factors, there are other factors that may have affected treatment selection that were not incorporated, including some that are not available in the NCDB, such as patient performance status and medical contraindications to chemotherapy. Second, although the goal of this study was to characterize patterns of care in the United States for patients with large, node-negative NSCLC treated with definitive RT, the NCDB is not a comprehensive population-based dataset, and it includes data from CoC member institutions only. Although the NCDB does capture >70% of new cancer diagnoses in the United States, if practice patterns varied greatly between CoC member and non-CoC member sites, the overall described practice patterns may not perfectly reflect national trends.

Conclusions

Practice patterns vary greatly among patients with 5- to 7-cm node-negative NSCLC receiving definitive RT. A substantial proportion of patients were not treated in concordance with NCCN Guidelines (Version 3.2020) and received concurrent chemoRT. The proportion of patients receiving NCCN-nonadherent concurrent chemoRT did not vary over time. Although younger patients with large tumors treated at nonacademic medical centers were more likely to receive NCCN-nonadherent therapy, adherence to NCCN Guidelines was not associated with differences in OS.

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Submitted August 19, 2020; final revision received March 31, 2021; accepted for publication April 5, 2021.

Published online August 12, 2021.

Author contributions: Study concept: Schneider, Kole. Data acquisition: Stahl. Primary data analysis: Schneider, Kole. Manuscript preparation: Schneider, Kole. Support for statistical analyses: Oster. Contributed to data analysis and editing of the manuscript: All authors.

Disclosures: The authors have disclosed that they have not received any financial consideration from any person or organization to support the preparation, analysis, results, or discussion of this article.

Data availability statement: The primary dataset from the National Cancer Database is available publicly through the American College of Surgeons (https://www.facs.org/quality-programs/cancer/ncdb). The statistic codes used during the present study are available from the corresponding author on reasonable request.

Correspondence: Adam J. Kole, MD, PhD, Department of Radiation Oncology, University of Alabama at Birmingham, 1700 Sixth Avenue South, Birmingham, AL 35233. Email: akole@uabmc.edu
  • View in gallery

    Patterns of chemotherapy and radiotherapy use.

    Abbreviations: CFRT, conventionally fractionated radiotherapy; HFRT, hypofractionated radiotherapy; SBRT, stereotactic body radiotherapy.

  • View in gallery

    Trends in (A) chemotherapy and (B) radiotherapy use over time in our cohort. A statistically significant trend of increased use of SBRT (Spearman ρ = 0.1775; P<.001) and HFRT was found (Spearman ρ = 0.058; P=.010) with corresponding decreased use of CFRT (Spearman ρ = −0.1955; P<.001). Comparison of (C) chemotherapy and (D) radiotherapy use from 2004 through 2010 and 2011 through 2016.

    Abbreviations: CFRT, conventionally fractionated radiotherapy; HFRT, hypofractionated radiotherapy; SBRT, stereotactic body radiotherapy.

    * P<.001 by chi-square analysis.

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    Butts CA , Ding K , Seymour L , et al. Randomized phase III trial of vinorelbine plus cisplatin compared with observation in completely resected stage IB and II non-small-cell lung cancer: updated survival analysis of JBR-10. J Clin Oncol 2010;28:2934.

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    • PubMed
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